chr2-233682324-T-G

Position:

• chr2-233682324-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019077.3(UGT1A7):​c.387T>G​(p.Asn129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,612,848 control chromosomes in the GnomAD database, including 314,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N129R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (28597 hom., cov: 32)
  • Exomes 𝑓: 0.62 (285655 hom.)
• Consequence: UGT1A7 NM_019077.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -13.7

Genes affected

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]

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]

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1985556E-6).
• BP6: Variant 2-233682324-T-G is Benign according to our data. Variant chr2-233682324-T-G is described in ClinVar as [Benign]. Clinvar id is 440386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A7	NM_019077.3	c.387T>G	p.Asn129Lys	missense_variant	1/5	ENST00000373426.4
UGT1A10	NM_019075.4	c.855+44947T>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+63762T>G		intron_variant		ENST00000373450.5
UGT1A9	NM_021027.3	c.855+9535T>G		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A7	ENST00000373426.4	c.387T>G	p.Asn129Lys	missense_variant	1/5	1	NM_019077.3	P1
UGT1A10	ENST00000344644.10	c.855+44947T>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+9535T>G		intron_variant		1	NM_021027.3	P1
UGT1A8	ENST00000373450.5	c.855+63762T>G		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.613 AC: 92597 AN: 151158 Hom.: 28571 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.588 AC: 142291 AN: 242112 Hom.: 42917 AF XY: 0.595 AC XY: 77976 AN XY: 131126

Gnomad AFR exome AF: 0.621

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.423

Gnomad SAS exome AF: 0.651

Gnomad FIN exome AF: 0.691

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.622 AC: 909731 AN: 1461574 Hom.: 285655 Cov.: 101 AF XY: 0.624 AC XY: 453364 AN XY: 727060

Gnomad4 AFR exome AF: 0.625

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.574

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.611

GnomAD4 genome AF: 0.613 AC: 92673 AN: 151274 Hom.: 28597 Cov.: 32 AF XY: 0.612 AC XY: 45234 AN XY: 73874

Gnomad4 AFR AF: 0.624

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.652

Gnomad4 FIN AF: 0.699

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.587

Alfa AF: 0.595 Hom.: 7345

Bravo AF: 0.596

TwinsUK AF: 0.619 AC: 2295

ALSPAC AF: 0.649 AC: 2503

ExAC AF: 0.589 AC: 71531

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 12172214, 12122597, 11677206, 11037804) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0080
DANN	Benign	0.51
DEOGEN2	Benign	0.15	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.19	N
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.011
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.15		Gain of methylation at N129 (P = 0.0381);
MPC		0.12
ClinPred		0.032	T
GERP RS		-9.0
Varity_R		0.096
gMVP		0.21

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: rs17868323; hg19: chr2-234590970; COSMIC: COSV60830578; COSMIC: COSV60830578;