4-69107231-C-G

Variant names:

• chr4-69107231-C-G
• rs4292394
• NM_001074.4:c.1059C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001074.4(UGT2B7):​c.1059C>G​(p.Leu353Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,606,936 control chromosomes in the GnomAD database, including 209,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.59 (27852 hom., cov: 31)
  • Exomes 𝑓: 0.49 (181853 hom.)
• Consequence: UGT2B7 NM_001074.4 synonymous
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: -2.87
• Publications: 26 publications found

Genes affected

UGT2B7 (HGNC:12554): (UDP glucuronosyltransferase family 2 member B7) The protein encoded by this gene belongs to the UDP-glycosyltransferase (UGT) family. UGTs serve a major role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This protein is localized in the microsome membrane, and has unique specificity for 3,4-catechol estrogens and estriol, suggesting that it may play an important role in regulating the level and activity of these potent estrogen metabolites. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

ENSG00000299782 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2B7	NM_001074.4	c.1059C>G	p.Leu353Leu	synonymous_variant	Exon 4 of 6	ENST00000305231.12	NP_001065.2
UGT2B7	NM_001330719.2	c.1059C>G	p.Leu353Leu	synonymous_variant	Exon 4 of 5		NP_001317648.1
UGT2B7	NM_001349568.2	c.312C>G	p.Leu104Leu	synonymous_variant	Exon 5 of 7		NP_001336497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2B7	ENST00000305231.12	c.1059C>G	p.Leu353Leu	synonymous_variant	Exon 4 of 6	1	NM_001074.4	ENSP00000304811.7

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89584 AN: 151736 Hom.: 27802 Cov.: 31

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.597

GnomAD2 exomes AF: 0.562 AC: 140529 AN: 249856 AF XY: 0.549

Gnomad AFR exome AF: 0.770

Gnomad AMR exome AF: 0.722

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.492 AC: 716176 AN: 1455080 Hom.: 181853 Cov.: 44 AF XY: 0.492 AC XY: 355969 AN XY: 724032

African (AFR) AF: 0.773 AC: 25679 AN: 33234

American (AMR) AF: 0.715 AC: 31637 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 13229 AN: 25950

East Asian (EAS) AF: 0.703 AC: 27797 AN: 39528

South Asian (SAS) AF: 0.517 AC: 44395 AN: 85814

European-Finnish (FIN) AF: 0.579 AC: 30814 AN: 53184

Middle Eastern (MID) AF: 0.528 AC: 3015 AN: 5712

European-Non Finnish (NFE) AF: 0.459 AC: 508555 AN: 1107338

Other (OTH) AF: 0.517 AC: 31055 AN: 60062

GnomAD4 genome AF: 0.591 AC: 89691 AN: 151856 Hom.: 27852 Cov.: 31 AF XY: 0.598 AC XY: 44404 AN XY: 74208

African (AFR) AF: 0.766 AC: 31722 AN: 41406

American (AMR) AF: 0.665 AC: 10140 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1771 AN: 3464

East Asian (EAS) AF: 0.701 AC: 3625 AN: 5170

South Asian (SAS) AF: 0.555 AC: 2673 AN: 4820

European-Finnish (FIN) AF: 0.574 AC: 6039 AN: 10524

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31847 AN: 67920

Other (OTH) AF: 0.598 AC: 1260 AN: 2106

Alfa AF: 0.452 Hom.: 4410

Bravo AF: 0.607

Asia WGS AF: 0.637 AC: 2215 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.41
DANN	Benign	0.48
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4292394; hg19: chr4-69972949; COSMIC: COSV59442341;