rs56385016

Positions:

• chr2-233682323-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_019077.3(UGT1A7):​c.386A>G​(p.Asn129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00843 in 1,614,124 control chromosomes in the GnomAD database, including 82 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N129K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (76 hom.)
• Consequence: UGT1A7 NM_019077.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00496006).
• BP6: Variant 2-233682323-A-G is Benign according to our data. Variant chr2-233682323-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1330729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT1A7	NM_019077.3	c.386A>G	p.Asn129Ser	missense_variant	1/5	ENST00000373426.4
UGT1A10	NM_019075.4	c.855+44946A>G		intron_variant		ENST00000344644.10
UGT1A8	NM_019076.5	c.855+63761A>G		intron_variant		ENST00000373450.5
UGT1A9	NM_021027.3	c.855+9534A>G		intron_variant		ENST00000354728.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT1A7	ENST00000373426.4	c.386A>G	p.Asn129Ser	missense_variant	1/5	1	NM_019077.3	P1
UGT1A10	ENST00000344644.10	c.855+44946A>G		intron_variant		1	NM_019075.4	P1
UGT1A9	ENST00000354728.5	c.855+9534A>G		intron_variant		1	NM_021027.3	P1
UGT1A8	ENST00000373450.5	c.855+63761A>G		intron_variant		1	NM_019076.5	P1

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 980 AN: 152154 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00721 AC: 1806 AN: 250518 Hom.: 7 AF XY: 0.00724 AC XY: 982 AN XY: 135574

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00820

GnomAD4 exome AF: 0.00863 AC: 12623 AN: 1461852 Hom.: 76 Cov.: 98 AF XY: 0.00850 AC XY: 6184 AN XY: 727228

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.00980

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152272 Hom.: 6 Cov.: 33 AF XY: 0.00626 AC XY: 466 AN XY: 74478

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00734 Hom.: 4

Bravo AF: 0.00557

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00797 AC: 967

EpiCase AF: 0.00813

EpiControl AF: 0.00937

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely 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	0.066
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.0
DANN	Benign	0.68
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.73	N
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.020
Sift	Benign	0.44	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.070
MVP		0.23
MPC		0.091
ClinPred		0.0022	T
GERP RS		3.4
Varity_R		0.061
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs56385016; hg19: chr2-234590969;