4-69096671-C-G

Variant names:

• chr4-69096671-C-G
• rs777092380
• NM_001074.4:c.151C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001074.4(UGT2B7):​c.151C>G​(p.His51Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UGT2B7 NM_001074.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT2B7	NM_001074.4	c.151C>G	p.His51Asp	missense_variant	Exon 1 of 6	ENST00000305231.12	NP_001065.2
UGT2B7	NM_001330719.2	c.151C>G	p.His51Asp	missense_variant	Exon 1 of 5		NP_001317648.1
UGT2B7	NM_001349568.2	c.-26-1869C>G		intron_variant	Intron 2 of 6		NP_001336497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2B7	ENST00000305231.12	c.151C>G	p.His51Asp	missense_variant	Exon 1 of 6	1	NM_001074.4	ENSP00000304811.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	4.6	H;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-8.4	D;D;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.75		Loss of catalytic residue at R49 (P = 0.221);Loss of catalytic residue at R49 (P = 0.221);Loss of catalytic residue at R49 (P = 0.221);
MVP		0.48
MPC		0.21
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.96
gMVP		0.72

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: rs777092380; hg19: chr4-69962389;