chr4-69096657-T-C

Position:

• chr4-69096657-T-C

Variant summary

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

The NM_001074.4(UGT2B7):​c.137T>C​(p.Leu46Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,614,008 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (25 hom.)
• Consequence: UGT2B7 NM_001074.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 5.15

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036030054).
• BP6: Variant 4-69096657-T-C is Benign according to our data. Variant chr4-69096657-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 718812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT2B7	NM_001074.4	c.137T>C	p.Leu46Pro	missense_variant	1/6	ENST00000305231.12	NP_001065.2
UGT2B7	NM_001330719.2	c.137T>C	p.Leu46Pro	missense_variant	1/5		NP_001317648.1
UGT2B7	NM_001349568.2	c.-26-1883T>C		intron_variant			NP_001336497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT2B7	ENST00000305231.12	c.137T>C	p.Leu46Pro	missense_variant	1/6	1	NM_001074.4	ENSP00000304811	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00262 AC: 658 AN: 251426 Hom.: 0 AF XY: 0.00256 AC XY: 348 AN XY: 135878

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00459 AC: 6710 AN: 1461754 Hom.: 25 Cov.: 31 AF XY: 0.00453 AC XY: 3292 AN XY: 727172

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00228

Gnomad4 NFE exome AF: 0.00562

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74452

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00455 Hom.: 0

Bravo AF: 0.00274

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00270 AC: 328

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2018

- -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	4.6	H;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.5	D;D;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MVP		0.63
MPC		0.22
ClinPred		0.14	T
GERP RS		1.2
Varity_R		0.97
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61361928; hg19: chr4-69962375; COSMIC: COSV100535388;