4-68567944-C-T

Position:

• chr4-68567944-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077.4(UGT2B17):​c.541G>A​(p.Val181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,380,688 control chromosomes in the GnomAD database, including 417 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (188 hom., cov: 20)
  • Exomes 𝑓: 0.00078 (229 hom.)
• Consequence: UGT2B17 NM_001077.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.91

Genes affected

UGT2B17 (HGNC:12547): (UDP glucuronosyltransferase family 2 member B17) This gene encodes a member of the uridine diphosphoglucuronosyltransferase protein family. The encoded enzyme catalyzes the transfer of glucuronic acid from uridine diphosphoglucuronic acid to a diverse array of substrates including steroid hormones and lipid-soluble drugs. This process, known as glucuronidation, is an intermediate step in the metabolism of steroids. Copy number variation in this gene is associated with susceptibility to osteoporosis.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039244294).
• BP6: Variant 4-68567944-C-T is Benign according to our data. Variant chr4-68567944-C-T is described in ClinVar as [Benign]. Clinvar id is 787028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00785 (995/126722) while in subpopulation AFR AF= 0.0259 (962/37126). AF 95% confidence interval is 0.0246. There are 188 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 188 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT2B17	NM_001077.4	c.541G>A	p.Val181Ile	missense_variant	2/7	ENST00000317746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT2B17	ENST00000317746.3	c.541G>A	p.Val181Ile	missense_variant	2/7	1	NM_001077.4	P1
UGT2B17	ENST00000684088.1	c.-26-2224G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 990 AN: 126650 Hom.: 186 Cov.: 20

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000350

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00365

Gnomad NFE AF: 0.0000335

Gnomad OTH AF: 0.00404

GnomAD3 exomes AF: 0.00243 AC: 488 AN: 201108 Hom.: 102 AF XY: 0.00180 AC XY: 195 AN XY: 108290

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000694

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000775 AC: 972 AN: 1253966 Hom.: 229 Cov.: 29 AF XY: 0.000687 AC XY: 426 AN XY: 620410

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000338

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000442

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00785 AC: 995 AN: 126722 Hom.: 188 Cov.: 20 AF XY: 0.00778 AC XY: 471 AN XY: 60520

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00178

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000335

Gnomad4 OTH AF: 0.00400

ESP6500AA AF: 0.0328 AC: 137

ESP6500EA AF: 0.000127 AC: 1

ExAC AF: 0.00296 AC: 310

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

UGT2B17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0020
DANN	Benign	0.13
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.86	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	0.49	T
Vest4		0.069
MVP		0.14
MPC		0.073
ClinPred		0.0098	T
GERP RS		-5.3
Varity_R		0.018
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs72551386; hg19: chr4-69433662;