rs566283411

Variant names:

• chr20-58440983-GTTC-G
• rs566283411
• NM_004738.5:c.479_481delCTT

Your query was ambiguous. Multiple possible variants found:

• chr20-58440983-GTTC-G
• chr20-58440983-GTTC-GTTCTTC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_004738.5(VAPB):​c.479_481delCTT​(p.Ser160del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0027 in 1,614,114 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: VAPB NM_004738.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 5.81
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004738.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 20-58440983-GTTC-G is Benign according to our data. Variant chr20-58440983-GTTC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338931.
• BS2: High AC in GnomAd4 at 241 AD gene.

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.479_481delCTT	p.Ser160del	disruptive_inframe_deletion	Exon 5 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.212-3088_212-3086delCTT		intron	N/A	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.525_527delCTT		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.479_481delCTT	p.Ser160del	disruptive_inframe_deletion	Exon 5 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.212-3088_212-3086delCTT		intron	N/A	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.539_541delCTT	p.Ser180del	disruptive_inframe_deletion	Exon 6 of 7	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00168 AC: 421 AN: 251172 AF XY: 0.00164

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00282 AC: 4117 AN: 1461844 Hom.: 11 AF XY: 0.00274 AC XY: 1994 AN XY: 727222

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00176 AC: 94 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00345 AC: 3837 AN: 1111988

Other (OTH) AF: 0.00202 AC: 122 AN: 60396

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74438

African (AFR) AF: 0.000602 AC: 25 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant (2)
-	-	2	not specified (2)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spinal Muscular Atrophy, Dominant (1)
-	-	1	VAPB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs566283411; hg19: chr20-57016039;