Genetic Variant NM_004738.5:c.-159_-158insCC (chr20-58389301-G-GCC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004738.5(VAPB):c.-159_-158insCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VAPB
NM_004738.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -1.63

Publications

0 publications found

Variant links:

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

VAPB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VAPB	NM_004738.5	MANE Select	c.-159_-158insCC	5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
VAPB	NM_001195677.2		c.-159_-158insCC	5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
VAPB	NR_036633.2		n.73_74insCC	non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-159_-158insCC	5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
VAPB	ENST00000903510.1		c.-159_-158insCC	5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
VAPB	ENST00000903509.1		c.-159_-158insCC	5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

Frequencies

GnomAD3 genomes

AF:

0.000568

AC:

AN:

132126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000212

Gnomad AMI

AF:

0.00129

Gnomad AMR

AF:

0.000142

Gnomad ASJ

AF:

0.000309

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00174

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000792

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000332

AC:

AN:

120352

AF XY:

0.0000453

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.0000460

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000202

AC:

109

AN:

540450

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

291290

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000818

AC:

AN:

12222

American (AMR)

AF:

0.0000639

AC:

AN:

31318

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

17364

East Asian (EAS)

AF:

0.00

AC:

AN:

25640

South Asian (SAS)

AF:

0.000147

AC:

AN:

61432

European-Finnish (FIN)

AF:

0.000269

AC:

AN:

33492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2224

European-Non Finnish (NFE)

AF:

0.000231

AC:

AN:

329486

Other (OTH)

AF:

0.000367

AC:

AN:

27272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.320

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000568

AC:

AN:

132126

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

AN XY:

64284

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000212

AC:

AN:

33028

American (AMR)

AF:

0.000142

AC:

AN:

14088

Ashkenazi Jewish (ASJ)

AF:

0.000309

AC:

AN:

3234

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.000220

AC:

AN:

4550

European-Finnish (FIN)

AF:

0.00174

AC:

AN:

8602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000792

AC:

AN:

60588

Other (OTH)

AF:

0.00

AC:

AN:

1880

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic Lateral Sclerosis, Dominant (1)

Spinal Muscular Atrophy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over