chr4-69098620-T-C

Variant names:

• chr4-69098620-T-C
• rs7439366
• NM_001074.4:c.802T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001074.4(UGT2B7):​c.802T>C​(p.Tyr268His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,610,326 control chromosomes in the GnomAD database, including 209,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y268D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.58 (25993 hom., cov: 30)
  • Exomes 𝑓: 0.49 (183153 hom.)
• Consequence: UGT2B7 NM_001074.4 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 2.01
• Publications: 261 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:58802):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.89177E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001074.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2B7	NM_001074.4	MANE Select	c.802T>C	p.Tyr268His	missense	Exon 2 of 6	NP_001065.2	P16662
	UGT2B7	NM_001330719.2		c.802T>C	p.Tyr268His	missense	Exon 2 of 5	NP_001317648.1	E9PBP8
	UGT2B7	NM_001349568.2		c.55T>C	p.Tyr19His	missense	Exon 3 of 7	NP_001336497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2B7	ENST00000305231.12	TSL:1 MANE Select	c.802T>C	p.Tyr268His	missense	Exon 2 of 6	ENSP00000304811.7	P16662
	UGT2B7	ENST00000868341.1		c.802T>C	p.Tyr268His	missense	Exon 2 of 7	ENSP00000538400.1
	UGT2B7	ENST00000868343.1		c.802T>C	p.Tyr268His	missense	Exon 2 of 7	ENSP00000538402.1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 86872 AN: 150978 Hom.: 25947 Cov.: 30

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.572

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.564 AC: 140844 AN: 249590 AF XY: 0.554

Gnomad AFR exome AF: 0.714

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.508

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: 0.494 AC: 720506 AN: 1459228 Hom.: 183153 Cov.: 54 AF XY: 0.495 AC XY: 359042 AN XY: 725826

African (AFR) AF: 0.716 AC: 23831 AN: 33302

American (AMR) AF: 0.713 AC: 31691 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13267 AN: 26058

East Asian (EAS) AF: 0.703 AC: 27824 AN: 39570

South Asian (SAS) AF: 0.567 AC: 48660 AN: 85816

European-Finnish (FIN) AF: 0.578 AC: 30866 AN: 53390

Middle Eastern (MID) AF: 0.527 AC: 3036 AN: 5760

European-Non Finnish (NFE) AF: 0.459 AC: 510152 AN: 1110578

Other (OTH) AF: 0.517 AC: 31179 AN: 60280

GnomAD4 genome AF: 0.576 AC: 86973 AN: 151098 Hom.: 25993 Cov.: 30 AF XY: 0.584 AC XY: 43110 AN XY: 73774

African (AFR) AF: 0.712 AC: 29289 AN: 41162

American (AMR) AF: 0.659 AC: 10016 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1769 AN: 3456

East Asian (EAS) AF: 0.697 AC: 3543 AN: 5080

South Asian (SAS) AF: 0.604 AC: 2896 AN: 4796

European-Finnish (FIN) AF: 0.573 AC: 5992 AN: 10464

Middle Eastern (MID) AF: 0.577 AC: 165 AN: 286

European-Non Finnish (NFE) AF: 0.468 AC: 31634 AN: 67660

Other (OTH) AF: 0.587 AC: 1230 AN: 2096

Alfa AF: 0.517 Hom.: 12758

Bravo AF: 0.590

TwinsUK AF: 0.452 AC: 1676

ALSPAC AF: 0.451 AC: 1739

ESP6500AA AF: 0.282 AC: 1242

ESP6500EA AF: 0.125 AC: 1078

ExAC AF: 0.560 AC: 67949

Asia WGS AF: 0.655 AC: 2275 AN: 3478

EpiCase AF: 0.490

EpiControl AF: 0.481

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Tramadol response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.4
DANN	Benign	0.68
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000099	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	3.3	N
REVEL	Benign	0.066
Sift	Benign	0.56	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.025
ClinPred		0.00043	T
GERP RS		1.8
Varity_R		0.023
gMVP		0.41
Mutation Taster		=99/1	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: rs7439366; hg19: chr4-69964338; COSMIC: COSV59443267;