Genetic Variant VPS26B:p.Ala94Ser (chr11-134234953-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_052875.5(VPS26B):c.280G>T(p.Ala94Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

VPS26B
NM_052875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

VPS26B (HGNC:28119): (VPS26 retromer complex component B) Predicted to be involved in intracellular protein transport and retrograde transport, endosome to Golgi. Predicted to act upstream of or within cellular response to interferon-gamma. Predicted to be located in early endosome and late endosome. Predicted to be part of retromer complex. Predicted to be active in endosome. [provided by Alliance of Genome Resources, Apr 2022]

VPS26B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS26B	NM_052875.5 link	c.280G>T	p.Ala94Ser	missense_variant	Exon 2 of 6	ENST00000281187.10	NP_443107.1	Q4G0F5A0A024R3L9
VPS26B	XM_011542565.4 link	c.280G>T	p.Ala94Ser	missense_variant	Exon 2 of 4		XP_011540867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS26B	ENST00000281187.10 link	c.280G>T	p.Ala94Ser	missense_variant	Exon 2 of 6	1	NM_052875.5	ENSP00000281187.5		Q4G0F5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251386

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135856

show subpopulations

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 SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280G>T (p.A94S) alteration is located in exon 2 (coding exon 2) of the VPS26B gene. This alteration results from a G to T substitution at nucleotide position 280, causing the alanine (A) at amino acid position 94 to be replaced by a serine (S). 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

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Benign

0.0045

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

D;.

REVEL

Uncertain

0.35

Sift

Benign

0.065

T;.

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.65

Gain of disorder (P = 0.0186);Gain of disorder (P = 0.0186);

MVP

0.29

MPC

2.0

ClinPred

0.50

GERP RS

5.6

Varity_R

0.24

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over