chr20-58389472-G-A

Position:

• chr20-58389472-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004738.5(VAPB):​c.13G>A​(p.Glu5Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,444,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25100964).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAPB	NM_004738.5	c.13G>A	p.Glu5Lys	missense_variant	1/6	ENST00000475243.6
VAPB	NM_001195677.2	c.13G>A	p.Glu5Lys	missense_variant	1/3
VAPB	NR_036633.2	n.244G>A		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3	n.244G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPB	ENST00000475243.6	c.13G>A	p.Glu5Lys	missense_variant	1/6	1	NM_004738.5	P1
VAPB	ENST00000395802.7	c.13G>A	p.Glu5Lys	missense_variant	1/3	1
VAPB	ENST00000265619.6	n.98G>A		non_coding_transcript_exon_variant	1/6	2
VAPB	ENST00000520497.1	c.13G>A	p.Glu5Lys	missense_variant, NMD_transcript_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000448 AC: 1 AN: 223218 Hom.: 0 AF XY: 0.00000824 AC XY: 1 AN XY: 121392

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: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1444960 Hom.: 0 Cov.: 32 AF XY: 0.00000836 AC XY: 6 AN XY: 717520

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with VAPB-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 5 of the VAPB protein (p.Glu5Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	0.079
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.14
Sift	Benign	0.065	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.025	B;B
Vest4		0.46
MutPred		0.33		Gain of methylation at E5 (P = 0.0079);Gain of methylation at E5 (P = 0.0079);
MVP		0.23
MPC		0.52
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.72
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: rs777026649; hg19: chr20-56964528;