Genetic Variant MAVS:p.Arg218Cys (chr20-3864282-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020746.5(MAVS):c.652C>T(p.Arg218Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,611,608 control chromosomes in the GnomAD database, including 16,102 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R218H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1105 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14997 hom. )

Consequence

MAVS
NM_020746.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.931

Publications

17 publications found

Variant links:

Genes affected

MAVS (HGNC:29233): (mitochondrial antiviral signaling protein) This gene encodes an intermediary protein necessary in the virus-triggered beta interferon signaling pathways. It is required for activation of transcription factors which regulate expression of beta interferon and contributes to antiviral innate immunity. [provided by RefSeq, Jul 2020]

MAVS links:

PANK2-AS1 (HGNC:40732): (PANK2 antisense RNA 1)

PANK2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014338195).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAVS	NM_020746.5 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 6 of 7	ENST00000428216.4	NP_065797.2	Q7Z434-1
MAVS	NM_001206491.2 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 5 of 6		NP_001193420.1	Q7Z434-4
MAVS	NM_001385663.1 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 7 of 8		NP_001372592.1
MAVS	NR_037921.2 link	n.616C>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAVS	ENST00000428216.4 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 6 of 7	1	NM_020746.5	ENSP00000401980.2	Q7Z434-1
MAVS	ENST00000416600.6 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 5 of 6	1		ENSP00000413749.2	Q7Z434-4
PANK2-AS1	ENST00000725518.1 link	n.426-1392G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16001

AN:

152048

Hom.:

1105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.127

GnomAD2 exomes

AF:

0.109

AC:

27058

AN:

248682

AF XY:

0.110

show subpopulations

Gnomad AFR exome

AF:

0.0264

Gnomad AMR exome

AF:

0.0785

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.136

AC:

198980

AN:

1459442

Hom.:

14997

Cov.:

AF XY:

0.135

AC XY:

97700

AN XY:

725846

show subpopulations

African (AFR)

AF:

0.0251

AC:

839

AN:

33442

American (AMR)

AF:

0.0830

AC:

3685

AN:

44412

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3683

AN:

25866

East Asian (EAS)

AF:

0.00103

AC:

AN:

39686

South Asian (SAS)

AF:

0.0371

AC:

3197

AN:

86058

European-Finnish (FIN)

AF:

0.112

AC:

5977

AN:

53284

Middle Eastern (MID)

AF:

0.140

AC:

807

AN:

5746

European-Non Finnish (NFE)

AF:

0.156

AC:

173104

AN:

1110672

Other (OTH)

AF:

0.127

AC:

7647

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

9857

19713

29570

39426

49283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5854

11708

17562

23416

29270

<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

AF:

0.105

AC:

15996

AN:

152166

Hom.:

1105

Cov.:

AF XY:

0.102

AC XY:

7551

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0284

AC:

1178

AN:

41520

American (AMR)

AF:

0.110

AC:

1684

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

521

AN:

3468

East Asian (EAS)

AF:

0.00193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0346

AC:

167

AN:

4824

European-Finnish (FIN)

AF:

0.108

AC:

1143

AN:

10606

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10819

AN:

67962

Other (OTH)

AF:

0.125

AC:

265

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

739

1477

2216

2954

3693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.139

Hom.:

3582

Bravo

AF:

0.103

TwinsUK

AF:

0.138

AC:

513

ALSPAC

AF:

0.144

AC:

556

ESP6500AA

AF:

0.0384

AC:

169

ESP6500EA

AF:

0.165

AC:

1418

ExAC

AF:

0.110

AC:

13311

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.168

EpiControl

AF:

0.167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

-0.93

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Benign

0.035

Sift

Benign

0.14

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.015

.;B

Vest4

0.17

MPC

0.19

ClinPred

0.041

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.085

gMVP

0.20

Mutation Taster

=79/21

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over