17-39966427-G-T

Variant names:

• chr17-39966427-G-T
• rs7212938
• NM_178171.5:c.382G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178171.5(GSDMA):​c.382G>T​(p.Val128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,601,404 control chromosomes in the GnomAD database, including 225,281 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (28849 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196432 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.604
• Publications: 82 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.293947E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 11		XP_016879991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 12	5		ENSP00000490739.1
GSDMA	ENST00000577447.1	c.382G>T	p.Val128Leu	missense_variant	Exon 3 of 4	4		ENSP00000461985.1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91043 AN: 151850 Hom.: 28793 Cov.: 32

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.579

GnomAD2 exomes AF: 0.522 AC: 125415 AN: 240256 AF XY: 0.525

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.503

Gnomad FIN exome AF: 0.618

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.517 AC: 748731 AN: 1449436 Hom.: 196432 Cov.: 38 AF XY: 0.517 AC XY: 372701 AN XY: 720732

African (AFR) AF: 0.831 AC: 27188 AN: 32702

American (AMR) AF: 0.363 AC: 15026 AN: 41352

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15180 AN: 25624

East Asian (EAS) AF: 0.506 AC: 20031 AN: 39562

South Asian (SAS) AF: 0.528 AC: 44916 AN: 85042

European-Finnish (FIN) AF: 0.608 AC: 32424 AN: 53322

Middle Eastern (MID) AF: 0.608 AC: 3351 AN: 5508

European-Non Finnish (NFE) AF: 0.505 AC: 558780 AN: 1106498

Other (OTH) AF: 0.532 AC: 31835 AN: 59826

GnomAD4 genome AF: 0.600 AC: 91154 AN: 151968 Hom.: 28849 Cov.: 32 AF XY: 0.603 AC XY: 44796 AN XY: 74268

African (AFR) AF: 0.817 AC: 33870 AN: 41480

American (AMR) AF: 0.494 AC: 7546 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2048 AN: 3466

East Asian (EAS) AF: 0.504 AC: 2597 AN: 5156

South Asian (SAS) AF: 0.541 AC: 2604 AN: 4814

European-Finnish (FIN) AF: 0.611 AC: 6447 AN: 10552

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.503 AC: 34183 AN: 67916

Other (OTH) AF: 0.578 AC: 1220 AN: 2110

Alfa AF: 0.535 Hom.: 55600

Bravo AF: 0.594

TwinsUK AF: 0.499 AC: 1849

ALSPAC AF: 0.508 AC: 1957

ESP6500AA AF: 0.810 AC: 3285

ESP6500EA AF: 0.502 AC: 4194

ExAC AF: 0.525 AC: 63510

EpiCase AF: 0.515

EpiControl AF: 0.505

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.47
DANN	Benign	0.90
DEOGEN2	Benign	0.0028	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.27	.;T;T
MetaRNN	Benign	0.000023	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N;N;.
PhyloP100		-0.60
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.1	.;N;.
REVEL	Benign	0.047
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0	B;B;.
Vest4		0.045
MutPred		0.63		Loss of methylation at K123 (P = 0.1247);Loss of methylation at K123 (P = 0.1247);Loss of methylation at K123 (P = 0.1247);
MPC		0.070
ClinPred		0.0013	T
GERP RS		-2.3
Varity_R		0.044
gMVP		0.081
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7212938; hg19: chr17-38122680; COSMIC: COSV56975670;