Genetic Variant VMAC:p.Glu34Lys (chr19-5904990-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001017921.4(VMAC):c.100G>A(p.Glu34Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000762 in 1,311,802 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: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

VMAC
NM_001017921.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28018013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4 link	c.100G>A	p.Glu34Lys	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.100G>A	p.Glu34Lys	missense_variant	Exon 1 of 2	1	NM_001017921.4	ENSP00000343348.2		Q2NL98
ENSG00000267314	ENST00000588891.1 link	n.100G>A		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000468419.1		K7ERU9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1311802

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

646052

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26120

American (AMR)

AF:

0.00

AC:

AN:

23368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22220

East Asian (EAS)

AF:

0.0000347

AC:

AN:

28818

South Asian (SAS)

AF:

0.00

AC:

AN:

70446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3942

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050060

Other (OTH)

AF:

0.00

AC:

AN:

54394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.100G>A (p.E34K) alteration is located in exon 1 (coding exon 1) of the VMAC gene. This alteration results from a G to A substitution at nucleotide position 100, causing the glutamic acid (E) at amino acid position 34 to be replaced by a lysine (K). 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

Uncertain

0.43

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

PhyloP100

4.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.2

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.96

Vest4

0.35

MutPred

0.36

Gain of MoRF binding (P = 0.002);

MVP

0.072

MPC

1.4

ClinPred

0.98

GERP RS

4.6

PromoterAI

-0.0076

Neutral

(source)

Varity_R

0.53

gMVP

0.49

Mutation Taster

=79/21

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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chr19-5904990-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over