17-81688716-G-T

Position:

• chr17-81688716-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004712.5(HGS):​c.304G>T​(p.Val102Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HGS NM_004712.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

Genes affected

HGS (HGNC:4897): (hepatocyte growth factor-regulated tyrosine kinase substrate) The protein encoded by this gene regulates endosomal sorting and plays a critical role in the recycling and degradation of membrane receptors. The encoded protein sorts monoubiquitinated membrane proteins into the multivesicular body, targeting these proteins for lysosome-dependent degradation. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21363786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGS	NM_004712.5	c.304G>T	p.Val102Leu	missense_variant	5/22	ENST00000329138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGS	ENST00000329138.9	c.304G>T	p.Val102Leu	missense_variant	5/22	1	NM_004712.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jun 27, 2023

The c.304G>T (p.V102L) alteration is located in exon 5 (coding exon 5) of the HGS gene. This alteration results from a G to T substitution at nucleotide position 304, causing the valine (V) at amino acid position 102 to be replaced by a leucine (L). 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	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.20
MutPred		0.44		.;Loss of MoRF binding (P = 0.1029);.;
MVP		0.76
MPC		2.1
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr17-79655746;