rs1555813003

chr20-58418347-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_004738.5(VAPB):c.195C>A(p.Ala65=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAPB NM_004738.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.646

Genes affected

VAPB (HGNC:12649): (VAMP associated protein B and C) The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 20-58418347-C-A is Benign according to our data. Variant chr20-58418347-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 534273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.646 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAPB	NM_004738.5	c.195C>A	p.Ala65=	synonymous_variant	2/6	ENST00000475243.6
VAPB	NM_001195677.2	c.195C>A	p.Ala65=	synonymous_variant	2/3
VAPB	NR_036633.2	n.426C>A		non_coding_transcript_exon_variant	2/4
VAPB	XR_001754433.3	n.426C>A		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPB	ENST00000475243.6	c.195C>A	p.Ala65=	synonymous_variant	2/6	1	NM_004738.5	P1
VAPB	ENST00000395802.7	c.195C>A	p.Ala65=	synonymous_variant	2/3	1
VAPB	ENST00000265619.6	n.493C>A		non_coding_transcript_exon_variant	3/6	2
VAPB	ENST00000520497.1	c.195C>A	p.Ala65=	synonymous_variant, NMD_transcript_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	7.7
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1555813003; hg19: chr20-56993403;