chr4-69096645-T-C

Variant names:

• chr4-69096645-T-C
• rs1577920813
• NM_001074.4:c.125T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001074.4(UGT2B7):​c.125T>C​(p.Ile42Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UGT2B7 NM_001074.4 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 6.83
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

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.125T>C	p.Ile42Thr	missense	Exon 1 of 6	NP_001065.2	P16662
	UGT2B7	NM_001330719.2		c.125T>C	p.Ile42Thr	missense	Exon 1 of 5	NP_001317648.1	E9PBP8
	UGT2B7	NM_001349568.2		c.-26-1895T>C		intron	N/A	NP_001336497.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2B7	ENST00000305231.12	TSL:1 MANE Select	c.125T>C	p.Ile42Thr	missense	Exon 1 of 6	ENSP00000304811.7	P16662
	UGT2B7	ENST00000868341.1		c.125T>C	p.Ile42Thr	missense	Exon 1 of 7	ENSP00000538400.1
	UGT2B7	ENST00000868343.1		c.125T>C	p.Ile42Thr	missense	Exon 1 of 7	ENSP00000538402.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.8
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.83		Loss of stability (P = 0.0191)
MVP		0.43
MPC		0.16
ClinPred		0.89	D
GERP RS		2.5
PromoterAI		-0.019	Neutral
Varity_R		0.65
gMVP		0.32
Mutation Taster		=72/28	polymorphism

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: rs1577920813; hg19: chr4-69962363;