rs281875284

Variant names:

• chr20-58418289-C-G
• NM_004738.5:c.137C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58418289-C-G
• chr20-58418289-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_004738.5(VAPB):​c.137C>G​(p.Thr46Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T46I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58418289-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.137C>G	p.Thr46Ser	missense_variant	Exon 2 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.137C>G	p.Thr46Ser	missense_variant	Exon 2 of 3		NP_001182606.1
VAPB	NR_036633.2	n.368C>G		non_coding_transcript_exon_variant	Exon 2 of 4
VAPB	XR_001754433.3	n.368C>G		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.137C>G	p.Thr46Ser	missense_variant	Exon 2 of 6	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7	c.137C>G	p.Thr46Ser	missense_variant	Exon 2 of 3	1		ENSP00000379147.3
VAPB	ENST00000265619.6	n.435C>G		non_coding_transcript_exon_variant	Exon 3 of 6	2
VAPB	ENST00000520497.1	n.137C>G		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.99	D;D
Vest4		0.91
MutPred		0.87		Loss of glycosylation at T46 (P = 0.0907);Loss of glycosylation at T46 (P = 0.0907);
MVP		0.96
MPC		1.3
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-56993345;