Genetic Variant GSDMA:p.Lys132Thr (chr17-39970484-A-C) – 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_178171.5(GSDMA):c.395A>C(p.Lys132Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000211 in 1,421,432 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GSDMA
NM_178171.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

Publications

0 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:

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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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178171.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDMA	NM_178171.5	MANE Select	c.395A>C	p.Lys132Thr	missense splice_region	Exon 4 of 12	NP_835465.2	Q96QA5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSDMA	ENST00000301659.9	TSL:1 MANE Select	c.395A>C	p.Lys132Thr	missense splice_region	Exon 4 of 12	ENSP00000301659.4	Q96QA5
GSDMA	ENST00000635792.1	TSL:5	c.395A>C	p.Lys132Thr	missense splice_region	Exon 4 of 12	ENSP00000490739.1	Q96QA5
GSDMA	ENST00000577447.1	TSL:4	c.395A>C	p.Lys132Thr	missense splice_region	Exon 4 of 4	ENSP00000461985.1	J3KRG2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000139

AC:

AN:

215520

AF XY:

0.00000851

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000105

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

AF:

0.00000211

AC:

AN:

1421432

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31434

American (AMR)

AF:

0.0000756

AC:

AN:

39682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24338

East Asian (EAS)

AF:

0.00

AC:

AN:

36568

South Asian (SAS)

AF:

0.00

AC:

AN:

81100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091768

Other (OTH)

AF:

0.00

AC:

AN:

58560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

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

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.029

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

PhyloP100

4.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.62

MutPred

0.64

Loss of ubiquitination at K132 (P = 0.0081)

MVP

0.43

MPC

0.45

ClinPred

0.81

GERP RS

4.5

Varity_R

0.27

gMVP

0.25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over