4-68537870-G-A

Position:

• chr4-68537870-G-A

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.1348C>T​(p.His450Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,371,496 control chromosomes in the GnomAD database, including 718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (345 hom., cov: 20)
  • Exomes 𝑓: 0.0013 (373 hom.)
• Consequence: UGT2B17 NM_001077.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.86

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=0.005250871).
• BP6: Variant 4-68537870-G-A is Benign according to our data. Variant chr4-68537870-G-A is described in ClinVar as [Benign]. Clinvar id is 789998.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 = 0.0138 (1746/126160) while in subpopulation AFR AF= 0.0451 (1666/36914). AF 95% confidence interval is 0.0433. There are 345 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 345 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT2B17	NM_001077.4	c.1348C>T	p.His450Tyr	missense_variant	7/7	ENST00000317746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT2B17	ENST00000317746.3	c.1348C>T	p.His450Tyr	missense_variant	7/7	1	NM_001077.4	P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1741 AN: 126092 Hom.: 343 Cov.: 20

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00488

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000117

Gnomad OTH AF: 0.00759

GnomAD3 exomes AF: 0.00389 AC: 773 AN: 198940 Hom.: 166 AF XY: 0.00278 AC XY: 297 AN XY: 106840

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000599

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00134 AC: 1667 AN: 1245336 Hom.: 373 Cov.: 29 AF XY: 0.00113 AC XY: 693 AN XY: 615108

Gnomad4 AFR exome AF: 0.0452

Gnomad4 AMR exome AF: 0.00261

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0138 AC: 1746 AN: 126160 Hom.: 345 Cov.: 20 AF XY: 0.0136 AC XY: 820 AN XY: 60198

Gnomad4 AFR AF: 0.0451

Gnomad4 AMR AF: 0.00488

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000117

Gnomad4 OTH AF: 0.00752

Alfa AF: 0.00749 Hom.: 23

ESP6500AA AF: 0.0447 AC: 187

ESP6500EA AF: 0.000382 AC: 3

ExAC AF: 0.00492 AC: 505

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.011
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Vest4		0.34
MVP		0.55
MPC		1.8
ClinPred		0.10	T
GERP RS		2.9
Varity_R		0.43
gMVP		0.28

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: rs72551385; hg19: chr4-69403588; COSMIC: COSV104619461;