17-39974934-C-A

Position:

• chr17-39974934-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178171.5(GSDMA):​c.941C>A​(p.Thr314Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,606,720 control chromosomes in the GnomAD database, including 162,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.41 (13394 hom., cov: 31)
  • Exomes 𝑓: 0.45 (149485 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031422079).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDMA	NM_178171.5	c.941C>A	p.Thr314Asn	missense_variant	10/12	ENST00000301659.9
GSDMA	XM_006721832.4	c.941C>A	p.Thr314Asn	missense_variant	10/12
GSDMA	XM_017024502.3	c.914C>A	p.Thr305Asn	missense_variant	9/11
GSDMA	XM_011524651.4	c.515C>A	p.Thr172Asn	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDMA	ENST00000301659.9	c.941C>A	p.Thr314Asn	missense_variant	10/12	1	NM_178171.5	P1
GSDMA	ENST00000635792.1	c.941C>A	p.Thr314Asn	missense_variant	10/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62978 AN: 151882 Hom.: 13385 Cov.: 31

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.416 AC: 102249 AN: 246038 Hom.: 21717 AF XY: 0.411 AC XY: 54891 AN XY: 133468

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.498

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.449 AC: 653523 AN: 1454720 Hom.: 149485 Cov.: 32 AF XY: 0.444 AC XY: 321371 AN XY: 723740

Gnomad4 AFR exome AF: 0.327

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.434

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.439

GnomAD4 genome AF: 0.415 AC: 63021 AN: 152000 Hom.: 13394 Cov.: 31 AF XY: 0.409 AC XY: 30408 AN XY: 74276

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.484

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.396

Alfa AF: 0.449 Hom.: 24959

Bravo AF: 0.411

TwinsUK AF: 0.474 AC: 1759

ALSPAC AF: 0.461 AC: 1778

ESP6500AA AF: 0.332 AC: 1260

ESP6500EA AF: 0.472 AC: 3880

ExAC AF: 0.418 AC: 50517

Asia WGS AF: 0.402 AC: 1398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0057	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.68	.;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.62	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.058
Sift	Benign	0.054	.;T
Sift4G	Uncertain	0.015	.;D
Polyphen		0.97	D;D
Vest4		0.18
MPC		0.24
ClinPred		0.013	T
GERP RS		4.0
Varity_R		0.090
gMVP		0.082

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

Other links and lift over

dbSNP: rs56030650; hg19: chr17-38131187; COSMIC: COSV56976382; COSMIC: COSV56976382;