20-58389484-A-G

Variant names:

• chr20-58389484-A-G
• rs766551604
• NM_004738.5:c.25A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004738.5(VAPB):​c.25A>G​(p.Ser9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,426 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain MSP (size 117) in uniprot entity VAPB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004738.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30618435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.25A>G	p.Ser9Gly	missense_variant	Exon 1 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.25A>G	p.Ser9Gly	missense_variant	Exon 1 of 3		NP_001182606.1
VAPB	NR_036633.2	n.256A>G		non_coding_transcript_exon_variant	Exon 1 of 4
VAPB	XR_001754433.3	n.256A>G		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.25A>G	p.Ser9Gly	missense_variant	Exon 1 of 6	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7	c.25A>G	p.Ser9Gly	missense_variant	Exon 1 of 3	1		ENSP00000379147.3
VAPB	ENST00000265619.6	n.110A>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
VAPB	ENST00000520497.1	n.25A>G		non_coding_transcript_exon_variant	Exon 1 of 4	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443426 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716718

Gnomad4 AFR exome AF: 0.0000305

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25A>G (p.S9G) alteration is located in exon 1 (coding exon 1) of the VAPB gene. This alteration results from a A to G substitution at nucleotide position 25, causing the serine (S) at amino acid position 9 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.093
Sift	Benign	0.18	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.17	B;B
Vest4		0.30
MutPred		0.38		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.34
MPC		0.46
ClinPred		0.24	T
GERP RS		4.4
Varity_R		0.36
gMVP		0.32

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: rs766551604; hg19: chr20-56964540;