20-58444159-G-T

Variant names:

• chr20-58444159-G-T
• rs786205553
• NM_004738.5:c.656G>T

Variant summary

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

The NM_004738.5(VAPB):​c.656G>T​(p.Gly219Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 9.02

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.656G>T	p.Gly219Val	missense_variant	Exon 6 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.294G>T	p.Arg98Ser	missense_variant	Exon 3 of 3		NP_001182606.1
VAPB	NR_036633.2	n.702G>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.656G>T	p.Gly219Val	missense_variant	Exon 6 of 6	1	NM_004738.5	ENSP00000417175.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727248

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000244 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 219 of the VAPB protein (p.Gly219Val). This variant is present in population databases (rs786205553, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with VAPB-related conditions. ClinVar contains an entry for this variant (Variation ID: 191163). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VAPB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.74	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.54	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.21		Loss of disorder (P = 0.0261);
MVP		0.81
MPC		1.5
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.53

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: rs786205553; hg19: chr20-57019215;