13-52423602-C-T

Variant names:

• chr13-52423602-C-T
• NM_016075.4:c.812G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016075.4(VPS36):​c.812G>A​(p.Cys271Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS36 NM_016075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

VPS36 (HGNC:20312): (vacuolar protein sorting 36 homolog) This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A similar protein complex in rat is associated with RNA polymerase elongation factor II. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS36	NM_016075.4	c.812G>A	p.Cys271Tyr	missense_variant	Exon 10 of 14	ENST00000378060.9	NP_057159.2
VPS36	NM_001282168.2	c.785G>A	p.Cys262Tyr	missense_variant	Exon 10 of 14		NP_001269097.1
VPS36	NM_001282169.2	c.638G>A	p.Cys213Tyr	missense_variant	Exon 10 of 14		NP_001269098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS36	ENST00000378060.9	c.812G>A	p.Cys271Tyr	missense_variant	Exon 10 of 14	1	NM_016075.4	ENSP00000367299.3
VPS36	ENST00000611132.4	c.638G>A	p.Cys213Tyr	missense_variant	Exon 10 of 14	1		ENSP00000484968.1
VPS36	ENST00000650274.1	n.812G>A		non_coding_transcript_exon_variant	Exon 10 of 15			ENSP00000497484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.812G>A (p.C271Y) alteration is located in exon 10 (coding exon 10) of the VPS36 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the cysteine (C) at amino acid position 271 to be replaced by a tyrosine (Y). 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	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.5	.;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.76		.;Gain of catalytic residue at C271 (P = 0.0288);
MVP		0.72
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr13-52997737;