rs3894194

Positions:

• chr17-39965740-G-A

Variant summary

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

The NM_178171.5(GSDMA):​c.53G>A​(p.Arg18Gln) 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 1,609,784 control chromosomes in the GnomAD database, including 162,085 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 (13320 hom., cov: 30)
  • Exomes 𝑓: 0.45 (148765 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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=3.8951635E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDMA	NM_178171.5	c.53G>A	p.Arg18Gln	missense_variant	2/12	ENST00000301659.9
GSDMA	XM_006721832.4	c.53G>A	p.Arg18Gln	missense_variant	2/12
GSDMA	XM_017024502.3	c.53G>A	p.Arg18Gln	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDMA	ENST00000301659.9	c.53G>A	p.Arg18Gln	missense_variant	2/12	1	NM_178171.5	P1
GSDMA	ENST00000635792.1	c.53G>A	p.Arg18Gln	missense_variant	2/12	5		P1
GSDMA	ENST00000577447.1	c.53G>A	p.Arg18Gln	missense_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62613 AN: 151754 Hom.: 13327 Cov.: 30

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.411

GnomAD3 exomes AF: 0.458 AC: 111394 AN: 243136 Hom.: 25996 AF XY: 0.455 AC XY: 59939 AN XY: 131808

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.562

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.450 AC: 655883 AN: 1457912 Hom.: 148765 Cov.: 47 AF XY: 0.450 AC XY: 326090 AN XY: 724894

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.561

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.542

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.446

GnomAD4 genome AF: 0.412 AC: 62610 AN: 151872 Hom.: 13320 Cov.: 30 AF XY: 0.411 AC XY: 30504 AN XY: 74216

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.466

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.411

Alfa AF: 0.439 Hom.: 17493

Bravo AF: 0.419

TwinsUK AF: 0.448 AC: 1661

ALSPAC AF: 0.441 AC: 1700

ESP6500AA AF: 0.295 AC: 1170

ESP6500EA AF: 0.456 AC: 3796

ExAC AF: 0.453 AC: 54715

Asia WGS AF: 0.456 AC: 1586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0054	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.00039	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L;L;.
MutationTaster	Benign	0.94	P
PrimateAI	Benign	0.44	T
Polyphen		0.016	B;B;.
Vest4		0.14
MPC		0.092
ClinPred		0.0051	T
GERP RS		3.3
Varity_R		0.072
gMVP		0.25

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

Other links and lift over

dbSNP: rs3894194; hg19: chr17-38121993; COSMIC: COSV56978411;