17-39974311-G-C

Variant names:

• chr17-39974311-G-C
• rs1285289410
• NM_178171.5:c.790G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178171.5(GSDMA):​c.790G>C​(p.Val264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2924237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.790G>C	p.Val264Leu	missense_variant	Exon 9 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.790G>C	p.Val264Leu	missense_variant	Exon 9 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.763G>C	p.Val255Leu	missense_variant	Exon 8 of 11		XP_016879991.1
GSDMA	XM_011524651.4	c.364G>C	p.Val122Leu	missense_variant	Exon 7 of 10		XP_011522953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.790G>C	p.Val264Leu	missense_variant	Exon 9 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.790G>C	p.Val264Leu	missense_variant	Exon 9 of 12	5		ENSP00000490739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 244022 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

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: 0.00000480 AC: 7 AN: 1459078 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 725470

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.790G>C (p.V264L) alteration is located in exon 9 (coding exon 8) of the GSDMA gene. This alteration results from a G to C substitution at nucleotide position 790, causing the valine (V) at amino acid position 264 to be replaced by a leucine (L). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	.;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.48	P;P
Vest4		0.45
MutPred		0.68		Loss of methylation at K261 (P = 0.0823);Loss of methylation at K261 (P = 0.0823);
MVP		0.13
MPC		0.19
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.54
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1285289410; hg19: chr17-38130564;