Genetic Variant VMAC:p.Glu25Ala (chr19-5904964-A-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001017921.4(VMAC):c.74A>C(p.Glu25Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,475,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

VMAC
NM_001017921.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

Publications

0 publications found

Variant links:

Genes affected

VMAC (HGNC:33803): (vimentin type intermediate filament associated coiled-coil protein) Predicted to be located in cytoplasm. Predicted to be active in type III intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

VMAC links:

ENSG00000267314 (HGNC:):

ENSG00000267314 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4034868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4 link	c.74A>C	p.Glu25Ala	missense_variant	Exon 1 of 2	ENST00000339485.4	NP_001017921.1	Q2NL98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMAC	ENST00000339485.4 link	c.74A>C	p.Glu25Ala	missense_variant	Exon 1 of 2	1	NM_001017921.4	ENSP00000343348.2		Q2NL98
ENSG00000267314	ENST00000588891.1 link	n.74A>C		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000468419.1		K7ERU9

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000405

AC:

AN:

73992

AF XY:

0.0000696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000225

AC:

298

AN:

1323618

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

145

AN XY:

652874

show subpopulations

African (AFR)

AF:

0.0000755

AC:

AN:

26506

American (AMR)

AF:

0.00

AC:

AN:

25142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23088

East Asian (EAS)

AF:

0.00

AC:

AN:

29026

South Asian (SAS)

AF:

0.00

AC:

AN:

72576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3944

European-Non Finnish (NFE)

AF:

0.000277

AC:

292

AN:

1055624

Other (OTH)

AF:

0.0000730

AC:

AN:

54832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.74A>C (p.E25A) alteration is located in exon 1 (coding exon 1) of the VMAC gene. This alteration results from a A to C substitution at nucleotide position 74, causing the glutamic acid (E) at amino acid position 25 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.2

PhyloP100

4.3

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.39

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.43

MVP

0.30

MPC

1.4

ClinPred

0.78

GERP RS

4.6

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.28

gMVP

0.34

Mutation Taster

=56/44

polymorphism

(source)

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

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19-5904964-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over