Variant chr17-39970484-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMA	NM_178171.5 linkuse as main transcript	c.395A>C	p.Lys132Thr	missense_variant, splice_region_variant	4/12	ENST00000301659.9	NP_835465.2	Q96QA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GSDMA	ENST00000301659.9 linkuse as main transcript	c.395A>C	p.Lys132Thr	missense_variant, splice_region_variant	4/12	1	NM_178171.5	ENSP00000301659.4	Q96QA5
GSDMA	ENST00000635792.1 linkuse as main transcript	c.395A>C	p.Lys132Thr	missense_variant, splice_region_variant	4/12	5		ENSP00000490739.1	Q96QA5
GSDMA	ENST00000577447.1 linkuse as main transcript	c.395A>C	p.Lys132Thr	missense_variant, splice_region_variant	4/4	4		ENSP00000461985.1	J3KRG2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000139

AC:

AN:

215520

Hom.:

AF XY:

0.00000851

AC XY:

AN XY:

117452

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000756

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2024

The c.395A>C (p.K132T) alteration is located in exon 4 (coding exon 3) of the GSDMA gene. This alteration results from a A to C substitution at nucleotide position 395, causing the lysine (K) at amino acid position 132 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Benign

0.64

DEOGEN2

Benign

0.029

T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

.;D;.

REVEL

Benign

0.23

Sift

Uncertain

0.0040

.;D;.

Sift4G

Uncertain

0.0060

.;D;D

Polyphen

1.0

D;D;.

Vest4

0.62

MutPred

0.64

Loss of ubiquitination at K132 (P = 0.0081);Loss of ubiquitination at K132 (P = 0.0081);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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over