Genetic Variant GSDMA:p.Val128Met (chr17-39966427-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_178171.5(GSDMA):c.382G>A(p.Val128Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000842 in 1,603,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

GSDMA
NM_178171.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.604

Publications

82 publications found

Variant links:

Genes affected

GSDMA (HGNC:13311): (gasdermin A) Predicted to enable phosphatidylinositol-4,5-bisphosphate binding activity; phosphatidylinositol-4-phosphate binding activity; and phosphatidylserine binding activity. Involved in apoptotic process. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

GSDMA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0087168515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 12	ENST00000301659.9	NP_835465.2	Q96QA5
GSDMA	XM_006721832.4 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 12		XP_006721895.1	Q96QA5
GSDMA	XM_017024502.3 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 11		XP_016879991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSDMA	ENST00000301659.9 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 12	1	NM_178171.5	ENSP00000301659.4	Q96QA5
GSDMA	ENST00000635792.1 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 12	5		ENSP00000490739.1	Q96QA5
GSDMA	ENST00000577447.1 link	c.382G>A	p.Val128Met	missense_variant	Exon 3 of 4	4		ENSP00000461985.1	J3KRG2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000412

AC:

AN:

240256

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000772

AC:

112

AN:

1451272

Hom.:

Cov.:

AF XY:

0.0000748

AC XY:

AN XY:

721644

show subpopulations

African (AFR)

AF:

0.0000611

AC:

AN:

32714

American (AMR)

AF:

0.00

AC:

AN:

41450

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25652

East Asian (EAS)

AF:

0.00245

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

85138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00000632

AC:

AN:

1107996

Other (OTH)

AF:

0.0000835

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000151

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41498

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00369

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67922

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

55600

ExAC

AF:

0.000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0027

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.39

.;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.97

N;N;.

PhyloP100

-0.60

PrimateAI

Benign

0.45

PROVEAN

Benign

1.8

.;N;.

REVEL

Benign

0.029

Sift

Benign

0.14

.;T;.

Sift4G

Uncertain

0.035

.;D;D

Polyphen

0.029

B;B;.

Vest4

0.13

MutPred

0.61

Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);Gain of disorder (P = 0.0694);

MVP

0.11

MPC

0.073

ClinPred

0.033

GERP RS

-2.3

Varity_R

0.041

gMVP

0.084

Mutation Taster

=100/0

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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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