10-69157112-T-C

Position:

• chr10-69157112-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001318946.2(VPS26A):​c.2T>C​(p.Met1?) variant causes a start lost 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: VPS26A NM_001318946.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

VPS26A (HGNC:12711): (VPS26 retromer complex component A) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

VPS26A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS26A	NM_004896.5	c.335T>C	p.Met112Thr	missense_variant	4/9	ENST00000263559.11	NP_004887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS26A	ENST00000263559.11	c.335T>C	p.Met112Thr	missense_variant	4/9	1	NM_004896.5	ENSP00000263559.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 20, 2023

The c.335T>C (p.M112T) alteration is located in exon 4 (coding exon 4) of the VPS26A gene. This alteration results from a T to C substitution at nucleotide position 335, causing the methionine (M) at amino acid position 112 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;T
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.1	N;N;N;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.10	N;N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.40	T;T;T;.
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.80
MutPred		0.28		Gain of phosphorylation at M112 (P = 0.0485);Gain of phosphorylation at M112 (P = 0.0485);Gain of phosphorylation at M112 (P = 0.0485);.;
MVP		0.36
MPC		0.43
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.35

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: rs991869628; hg19: chr10-70916868;