4-68537739-A-T

Position:

• chr4-68537739-A-T

Variant summary

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

The NM_001077.4(UGT2B17):​c.1479T>A​(p.Asp493Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000798 in 1,253,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: UGT2B17 NM_001077.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.367

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 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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UGT2B17	NM_001077.4	c.1479T>A	p.Asp493Glu	missense_variant	7/7	ENST00000317746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UGT2B17	ENST00000317746.3	c.1479T>A	p.Asp493Glu	missense_variant	7/7	1	NM_001077.4	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 7.98e-7 AC: 1 AN: 1253250 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 619348

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: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2024

The c.1479T>A (p.D493E) alteration is located in exon 6 (coding exon 6) of the UGT2B17 gene. This alteration results from a T to A substitution at nucleotide position 1479, causing the aspartic acid (D) at amino acid position 493 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.067
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0063	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.72
MutPred		0.92		Gain of helix (P = 0.2294);
MVP		0.45
MPC		1.9
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.68
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-69403457;