20-58445517-A-G

Variant names:

• chr20-58445517-A-G
• rs1802459
• NM_004738.5:c.*1282A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004738.5(VAPB):​c.*1282A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 454,294 control chromosomes in the GnomAD database, including 7,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2090 hom., cov: 32)
  • Exomes 𝑓: 0.17 (5060 hom.)
• Consequence: VAPB NM_004738.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.47
• Publications: 11 publications found

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]

VAPB Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• adult-onset proximal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 20-58445517-A-G is Benign according to our data. Variant chr20-58445517-A-G is described in ClinVar as Benign. ClinVar VariationId is 338947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	NM_004738.5	MANE Select	c.*1282A>G		3_prime_UTR	Exon 6 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.*1352A>G		3_prime_UTR	Exon 3 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.2060A>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.*1282A>G		3_prime_UTR	Exon 6 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.*1352A>G		3_prime_UTR	Exon 3 of 3	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.*1282A>G		3_prime_UTR	Exon 7 of 7	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23973 AN: 152026 Hom.: 2086 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.163 AC: 22236 AN: 136630 AF XY: 0.171

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0563

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.168 AC: 50753 AN: 302152 Hom.: 5060 Cov.: 0 AF XY: 0.179 AC XY: 30767 AN XY: 172210

African (AFR) AF: 0.159 AC: 1363 AN: 8548

American (AMR) AF: 0.0558 AC: 1521 AN: 27270

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 1860 AN: 10786

East Asian (EAS) AF: 0.317 AC: 2921 AN: 9210

South Asian (SAS) AF: 0.250 AC: 14874 AN: 59602

European-Finnish (FIN) AF: 0.250 AC: 3200 AN: 12790

Middle Eastern (MID) AF: 0.142 AC: 163 AN: 1150

European-Non Finnish (NFE) AF: 0.143 AC: 22681 AN: 158752

Other (OTH) AF: 0.155 AC: 2170 AN: 14044

GnomAD4 genome AF: 0.158 AC: 23983 AN: 152142 Hom.: 2090 Cov.: 32 AF XY: 0.166 AC XY: 12326 AN XY: 74356

African (AFR) AF: 0.154 AC: 6390 AN: 41526

American (AMR) AF: 0.0825 AC: 1262 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3468

East Asian (EAS) AF: 0.310 AC: 1605 AN: 5180

South Asian (SAS) AF: 0.255 AC: 1228 AN: 4816

European-Finnish (FIN) AF: 0.273 AC: 2880 AN: 10566

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9526 AN: 67970

Other (OTH) AF: 0.138 AC: 291 AN: 2114

Alfa AF: 0.137 Hom.: 1044

Bravo AF: 0.140

Asia WGS AF: 0.258 AC: 895 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Adult-onset proximal spinal muscular atrophy, autosomal dominant (1)
-	-	1	Amyotrophic lateral sclerosis type 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1802459; hg19: chr20-57020573; COSMIC: COSV55669315; COSMIC: COSV55669315;