13-52415877-C-G

Position:

• chr13-52415877-C-G

Variant summary

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

The NM_016075.4(VPS36):​c.1114G>C​(p.Val372Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.53

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]

THSD1 (HGNC:17754): (thrombospondin type 1 domain containing 1) The protein encoded by this gene contains a type 1 thrombospondin domain, which is found in a number of proteins involved in the complement pathway, as well as in extracellular matrix proteins. Alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Jan 2009]

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/exons	MANE	Protein	UniProt
VPS36	NM_016075.4	c.1114G>C	p.Val372Leu	missense_variant	14/14	ENST00000378060.9	NP_057159.2
VPS36	NM_001282168.2	c.1087G>C	p.Val363Leu	missense_variant	14/14		NP_001269097.1
VPS36	NM_001282169.2	c.940G>C	p.Val314Leu	missense_variant	14/14		NP_001269098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS36	ENST00000378060.9	c.1114G>C	p.Val372Leu	missense_variant	14/14	1	NM_016075.4	ENSP00000367299	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 26, 2024

The c.1114G>C (p.V372L) alteration is located in exon 14 (coding exon 14) of the VPS36 gene. This alteration results from a G to C substitution at nucleotide position 1114, causing the valine (V) at amino acid position 372 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0058	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.16
Sift	Uncertain	0.010	.;D
Sift4G	Benign	0.093	T;T
Polyphen		0.99	.;D
Vest4		0.59
MutPred		0.39		.;Gain of helix (P = 0.0854);
MVP		0.78
MPC		0.50
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.66
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: chr13-52990012;