20-58389427-C-G

Variant names:

• chr20-58389427-C-G
• rs201547974
• NM_004738.5:c.-33C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004738.5(VAPB):​c.-33C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,574,292 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (6 hom.)
• Consequence: VAPB NM_004738.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.25
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 20-58389427-C-G is Benign according to our data. Variant chr20-58389427-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 142 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.-33C>G		5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.-33C>G		5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.199C>G		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-33C>G		5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.-33C>G		5_prime_UTR	Exon 1 of 3	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.-33C>G		5_prime_UTR	Exon 1 of 7	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00140 AC: 272 AN: 194666 AF XY: 0.00169

Gnomad AFR exome AF: 0.000184

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.0000682

Gnomad FIN exome AF: 0.0000572

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.000878 AC: 1249 AN: 1422156 Hom.: 6 Cov.: 32 AF XY: 0.000908 AC XY: 640 AN XY: 704558

African (AFR) AF: 0.0000625 AC: 2 AN: 32002

American (AMR) AF: 0.00114 AC: 46 AN: 40246

Ashkenazi Jewish (ASJ) AF: 0.00882 AC: 223 AN: 25292

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37386

South Asian (SAS) AF: 0.00101 AC: 82 AN: 81014

European-Finnish (FIN) AF: 0.0000990 AC: 5 AN: 50506

Middle Eastern (MID) AF: 0.00899 AC: 46 AN: 5118

European-Non Finnish (NFE) AF: 0.000688 AC: 751 AN: 1091968

Other (OTH) AF: 0.00159 AC: 93 AN: 58624

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152136 Hom.: 1 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74384

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.00170 AC: 26 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 67976

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.000967

Asia WGS AF: 0.000581 AC: 2 AN: 3454

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		1.3
PromoterAI		-0.0037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism

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: rs201547974; hg19: chr20-56964483;