10-69133012-T-A

Variant names:

• chr10-69133012-T-A
• rs1252090102
• NM_004896.5:c.118T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004896.5(VPS26A):​c.118T>A​(p.Tyr40Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y40H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS26A NM_004896.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.98
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.118T>A	p.Tyr40Asn	missense	Exon 2 of 9	NP_004887.2
	VPS26A	NM_001035260.3		c.118T>A	p.Tyr40Asn	missense	Exon 2 of 8	NP_001030337.1	O75436-2
	VPS26A	NM_001318944.2		c.-10T>A		5_prime_UTR	Exon 2 of 10	NP_001305873.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS26A	ENST00000263559.11	TSL:1 MANE Select	c.118T>A	p.Tyr40Asn	missense	Exon 2 of 9	ENSP00000263559.6	O75436-1
	VPS26A	ENST00000949228.1		c.118T>A	p.Tyr40Asn	missense	Exon 2 of 10	ENSP00000619287.1
	VPS26A	ENST00000858435.1		c.118T>A	p.Tyr40Asn	missense	Exon 2 of 9	ENSP00000528494.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247656 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Benign	0.30	T
Polyphen		0.090	B
Vest4		0.71
MutPred		0.49		Gain of catalytic residue at Y40 (P = 0.0084)
MVP		0.17
MPC		0.85
ClinPred		0.93	D
GERP RS		5.4
PromoterAI		0.029	Neutral
Varity_R		0.70
gMVP		0.58
Mutation Taster		=23/77	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: rs1252090102; hg19: chr10-70892768;