Genetic Variant NM_178171.5:c.413C>G (chr17-39970502-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178171.5(GSDMA):c.413C>G(p.Pro138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Consequence

GSDMA
NM_178171.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21188647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 12	ENST00000301659.9	NP_835465.2	Q96QA5
GSDMA	XM_006721832.4 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 12		XP_006721895.1	Q96QA5
GSDMA	XM_017024502.3 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 11		XP_016879991.1
GSDMA	XM_011524651.4 link	c.-14C>G		5_prime_UTR_variant	Exon 2 of 10		XP_011522953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSDMA	ENST00000301659.9 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 12	1	NM_178171.5	ENSP00000301659.4	Q96QA5
GSDMA	ENST00000635792.1 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 12	5		ENSP00000490739.1	Q96QA5
GSDMA	ENST00000577447.1 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 4 of 4	4		ENSP00000461985.1	J3KRG2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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

GnomAD3 exomes

AF:

0.00000890

AC:

AN:

224624

Hom.:

AF XY:

0.00000816

AC XY:

AN XY:

122532

show subpopulations

Gnomad AFR exome

AF:

0.000147

Gnomad AMR exome

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

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

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413C>G (p.P138R) alteration is located in exon 4 (coding exon 3) of the GSDMA gene. This alteration results from a C to G substitution at nucleotide position 413, causing the proline (P) at amino acid position 138 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Benign

0.025

T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.14

Sift

Benign

0.16

.;T;.

Sift4G

Uncertain

0.0050

.;D;D

Polyphen

0.93

P;P;.

Vest4

0.65

MVP

0.59

MPC

0.39

ClinPred

0.52

GERP RS

5.6

Varity_R

0.11

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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