rs397978903

Positions:

• chr2-233761122-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The ENST00000305208.10(UGT1A1):​c.835A>T​(p.Asn279Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: UGT1A1 ENST00000305208.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 3.00

Genes affected

UGT1A1 (HGNC:12530): (UDP glucuronosyltransferase family 1 member A1) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The preferred substrate of this enzyme is bilirubin, although it also has moderate activity with simple phenols, flavones, and C18 steroids. Mutations in this gene result in Crigler-Najjar syndromes types I and II and in Gilbert syndrome. [provided by RefSeq, Jul 2008]

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [provided by RefSeq, Jul 2008]

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. [provided by RefSeq, Jul 2008]

UGT1A3 (HGNC:12535): (UDP glucuronosyltransferase family 1 member A3) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. Substrates of this enzyme include estrone, 2-hydroxyestrone, and metabolites of benzo alpha-pyrene. [provided by RefSeq, Jul 2008]

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenols. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A1	NM_000463.3	c.835A>T	p.Asn279Tyr	missense_variant	1/5	ENST00000305208.10	NP_000454.1
UGT1A6	NM_001072.4	c.862-5912A>T		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A4	NM_007120.3	c.868-5912A>T		intron_variant		ENST00000373409.8	NP_009051.1
UGT1A10	NM_019075.4	c.856-5912A>T		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-5912A>T		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.856-5912A>T		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.868-5912A>T		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A3	NM_019093.4	c.868-5912A>T		intron_variant		ENST00000482026.6	NP_061966.1
UGT1A9	NM_021027.3	c.856-5912A>T		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A1	ENST00000305208.10	c.835A>T	p.Asn279Tyr	missense_variant	1/5	1	NM_000463.3	ENSP00000304845	P1
UGT1A6	ENST00000305139.11	c.862-5912A>T		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-5912A>T		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.856-5912A>T		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A4	ENST00000373409.8	c.868-5912A>T		intron_variant		1	NM_007120.3	ENSP00000362508	P1
UGT1A5	ENST00000373414.4	c.868-5912A>T		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.856-5912A>T		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-5912A>T		intron_variant		1	NM_019076.5	ENSP00000362549	P1
UGT1A3	ENST00000482026.6	c.868-5912A>T		intron_variant		1	NM_019093.4	ENSP00000418532	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 249192 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.0000853 AC XY: 62 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UGT1A1 protein function. ClinVar contains an entry for this variant (Variation ID: 498039). This missense change has been observed in individuals with Crigler-Najjar syndrome type I or type II (PMID: 11013440, 17229650, 18058623). This variant is present in population databases (rs397978903, gnomAD 0.006%). This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 279 of the UGT1A1 protein (p.Asn279Tyr). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 22, 2020	The UGT1A1 c.835A>T; p.Asn279Tyr variant (rs397978903) is reported in the literature in several compound heterozygous individuals affected with Crigler-Najjar syndrome (D'Apolito 2007, Kadakol 2000, Perretti 2007). This variant is found on only seven chromosomes (7/249192 alleles) in the Genome Aggregation Database. The asparagine at codon 279 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.445). Due to limited information, the clinical significance of the p.Asn279Tyr variant is uncertain at this time. References: D'Apolito M et al. Seven novel mutations of the UGT1A1 gene in patients with unconjugated hyperbilirubinemia. Haematologica. 2007 Jan;92(1):133-4. Kadakol A et al. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. 2000 Oct;16(4):297-306. Perretti A et al. Clinical utility of electrophysiological evaluation in Crigler-Najjar syndrome. Neuropediatrics. 2007 Aug;38(4):173-8. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2017	- -

Crigler-Najjar syndrome, type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

UGT1A1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The UGT1A1 c.835A>T variant is predicted to result in the amino acid substitution p.Asn279Tyr. This variant was reported in the heterozygous state in two individuals who presented with Crigler-Najjar type II; both patients also carried the risk variant c.-41_-40dup (i.e., on the opposite allele) (D’Apolito et al. 2007. PubMed ID: 17229650; Perretti A et al 2007. PubMed ID: 18058623). This variant was also reported in the heterozygous state alongside a nonsense variant (c.1069C>T, p.Gln357Ter) in a patient with Crigler-Najjar type I (Kadakol A et al 2000. PubMed ID: 11013440). Although c.835A>T (p.Asn279Tyr) could be pathogenic, the clinical significance of this variant is classified as uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.0094	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.59
MVP		0.78
MPC		0.60
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397978903; hg19: chr2-234669768;