Genetic Variant VMAC:p.Arg21Gln (chr19-5904952-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017921.4(VMAC):c.62G>A(p.Arg21Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,327,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

VMAC
NM_001017921.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11312455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4 link	c.62G>A	p.Arg21Gln	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.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 2	1	NM_001017921.4	ENSP00000343348.2		Q2NL98
ENSG00000267314	ENST00000588891.1 link	n.62G>A		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000468419.1		K7ERU9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000262

AC:

AN:

76300

AF XY:

0.0000451

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1327876

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

655136

show subpopulations

African (AFR)

AF:

0.0000374

AC:

AN:

26706

American (AMR)

AF:

0.00

AC:

AN:

26044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23238

East Asian (EAS)

AF:

0.00

AC:

AN:

29144

South Asian (SAS)

AF:

0.00

AC:

AN:

73104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3932

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057676

Other (OTH)

AF:

0.0000182

AC:

AN:

55058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.82

M_CAP

Benign

0.063

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

2.9

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.64

REVEL

Benign

0.037

Sift

Benign

0.14

Sift4G

Uncertain

0.059

Polyphen

0.32

Vest4

0.23

MutPred

0.16

Loss of methylation at R21 (P = 0.0258);

MVP

0.030

MPC

0.56

ClinPred

0.069

GERP RS

2.5

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.086

gMVP

0.095

Mutation Taster

=83/17

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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19-5904952-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over