Genetic Variant VIRMA:p.Val940Asp (chr8-94512022-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015496.5(VIRMA):c.2819T>A(p.Val940Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V940A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VIRMA
NM_015496.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.64

Publications

1 publications found

Variant links:

Genes affected

VIRMA (HGNC:24500): (vir like m6A methyltransferase associated) Enables RNA binding activity. Involved in mRNA alternative polyadenylation and mRNA methylation. Located in cytosol and nuclear speck. Colocalizes with RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

VIRMA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIRMA	NM_015496.5 link	c.2819T>A	p.Val940Asp	missense_variant	Exon 12 of 24	ENST00000297591.10	NP_056311.2	Q69YN4-1
VIRMA	NM_183009.3 link	c.2819T>A	p.Val940Asp	missense_variant	Exon 12 of 13		NP_892121.1	Q69YN4-4
VIRMA	XM_047421677.1 link	c.1814T>A	p.Val605Asp	missense_variant	Exon 13 of 25		XP_047277633.1
VIRMA	XM_047421678.1 link	c.1814T>A	p.Val605Asp	missense_variant	Exon 8 of 20		XP_047277634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VIRMA	ENST00000297591.10 link	c.2819T>A	p.Val940Asp	missense_variant	Exon 12 of 24	1	NM_015496.5	ENSP00000297591.5	Q69YN4-1
VIRMA	ENST00000421249.2 link	c.2819T>A	p.Val940Asp	missense_variant	Exon 12 of 13	1		ENSP00000398390.2	Q69YN4-4
VIRMA	ENST00000521080.5 link	n.434T>A		non_coding_transcript_exon_variant	Exon 1 of 10	1
VIRMA	ENST00000522263.5 link	n.878T>A		non_coding_transcript_exon_variant	Exon 5 of 15	1		ENSP00000429909.1	H0YBN5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

212610

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1383212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686666

African (AFR)

AF:

0.00

AC:

AN:

29742

American (AMR)

AF:

0.00

AC:

AN:

37366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24252

East Asian (EAS)

AF:

0.00

AC:

AN:

34720

South Asian (SAS)

AF:

0.00

AC:

AN:

72450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072650

Other (OTH)

AF:

0.00

AC:

AN:

56416

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.90

L;L

PhyloP100

8.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.69

P;P

Vest4

0.86

MutPred

0.52

Gain of disorder (P = 0.0469);Gain of disorder (P = 0.0469);

MVP

0.41

MPC

1.1

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.87

Mutation Taster

=37/63

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over