10-69162473-A-G

Variant names:

• chr10-69162473-A-G
• rs1241932737
• NM_004896.5:c.619A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004896.5(VPS26A):​c.619A>G​(p.Met207Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS26A NM_004896.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004896.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS26A	NM_004896.5	MANE Select	c.619A>G	p.Met207Val	missense	Exon 6 of 9	NP_004887.2
	VPS26A	NM_001318944.2		c.598A>G	p.Met200Val	missense	Exon 7 of 10	NP_001305873.1
	VPS26A	NM_001318945.2		c.568A>G	p.Met190Val	missense	Exon 7 of 10	NP_001305874.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS26A	ENST00000263559.11	TSL:1 MANE Select	c.619A>G	p.Met207Val	missense	Exon 6 of 9	ENSP00000263559.6	O75436-1
	VPS26A	ENST00000949228.1		c.649A>G	p.Met217Val	missense	Exon 7 of 10	ENSP00000619287.1
	VPS26A	ENST00000858435.1		c.619A>G	p.Met207Val	missense	Exon 6 of 9	ENSP00000528494.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243880 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422028 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 709244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32298

American (AMR) AF: 0.00 AC: 0 AN: 42264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.00 AC: 0 AN: 84360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080448

Other (OTH) AF: 0.00 AC: 0 AN: 58938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.12	B
Vest4		0.73
MutPred		0.80		Loss of MoRF binding (P = 0.1367)
MVP		0.53
MPC		0.89
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.67
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1241932737; hg19: chr10-70922229;