20-58389427-C-G

Position:

• chr20-58389427-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 338927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAPB	NM_004738.5	c.-33C>G		5_prime_UTR_variant	1/6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.-33C>G		5_prime_UTR_variant	1/3		NP_001182606.1
VAPB	NR_036633.2	n.199C>G		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3	n.199C>G		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.-33C>G		5_prime_UTR_variant	1/6	1	NM_004738.5	ENSP00000417175	P1
VAPB	ENST00000395802.7	c.-33C>G		5_prime_UTR_variant	1/3	1		ENSP00000379147
VAPB	ENST00000265619.6	n.53C>G		non_coding_transcript_exon_variant	1/6	2
VAPB	ENST00000520497.1	c.-33C>G		5_prime_UTR_variant, NMD_transcript_variant	1/4	2		ENSP00000430426

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

GnomAD3 exomes AF: 0.00140 AC: 272 AN: 194666 Hom.: 1 AF XY: 0.00169 AC XY: 178 AN XY: 105368

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 SAS exome AF: 0.00104

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

Gnomad4 AFR exome AF: 0.0000625

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00882

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.0000990

Gnomad4 NFE exome AF: 0.000688

Gnomad4 OTH exome AF: 0.00159

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

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.000967

Asia WGS AF: 0.000581 AC: 2 AN: 3454

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

- -

Adult-onset proximal spinal muscular atrophy, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs201547974; hg19: chr20-56964483;