11-119067876-T-G

Variant names:

• chr11-119067876-T-G
• rs1480253653
• NM_021729.6:c.53T>G

Variant summary

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

The NM_021729.6(VPS11):​c.53T>G​(p.Val18Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS11 NM_021729.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

Genes affected

VPS11 (HGNC:14583): (VPS11 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps11 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS11	NM_021729.6	c.53T>G	p.Val18Gly	missense_variant	Exon 1 of 16	ENST00000621676.5	NP_068375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS11	ENST00000621676.5	c.53T>G	p.Val18Gly	missense_variant	Exon 1 of 16	1	NM_021729.6	ENSP00000481126.1
VPS11	ENST00000614944	c.-193T>G		5_prime_UTR_variant	Exon 1 of 16	2		ENSP00000481807.1
VPS11	ENST00000622309.4	n.54T>G		non_coding_transcript_exon_variant	Exon 1 of 13	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53T>G (p.V18G) alteration is located in exon 1 (coding exon 1) of the VPS11 gene. This alteration results from a T to G substitution at nucleotide position 53, causing the valine (V) at amino acid position 18 to be replaced by a glycine (G). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Benign	0.87
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.72	D
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.10	T
Vest4		0.59
MVP		0.58
GERP RS		4.0
gMVP		0.89

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: rs1480253653; hg19: chr11-118938587;