13-52450513-C-T

Position:

• chr13-52450513-C-T

Variant summary

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

The NM_016075.4(VPS36):​c.82G>A​(p.Asp28Asn) variant causes a missense change involving the alteration of a non-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: 2.47

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 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.82G>A	p.Asp28Asn	missense_variant	1/14	ENST00000378060.9	NP_057159.2
VPS36	NM_001282168.2	c.69+13G>A		intron_variant			NP_001269097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS36	ENST00000378060.9	c.82G>A	p.Asp28Asn	missense_variant	1/14	1	NM_016075.4	ENSP00000367299	P1
VPS36	ENST00000475375.1	n.116G>A		non_coding_transcript_exon_variant	1/4	2
VPS36	ENST00000650274.1	c.82G>A	p.Asp28Asn	missense_variant, NMD_transcript_variant	1/15			ENSP00000497484

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

Aug 15, 2023

The c.82G>A (p.D28N) alteration is located in exon 1 (coding exon 1) of the VPS36 gene. This alteration results from a G to A substitution at nucleotide position 82, causing the aspartic acid (D) at amino acid position 28 to be replaced by an asparagine (N). 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	0.51
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.74		Gain of ubiquitination at K32 (P = 0.0872);
MVP		0.64
MPC		1.3
ClinPred		0.98	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.62

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: chr13-53024648;