17-39971570-T-C

Variant names:

• chr17-39971570-T-C
• rs1420777690
• NM_178171.5:c.605T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178171.5(GSDMA):​c.605T>C​(p.Val202Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V202I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.605T>C	p.Val202Ala	missense_variant	Exon 5 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.605T>C	p.Val202Ala	missense_variant	Exon 5 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.605T>C	p.Val202Ala	missense_variant	Exon 5 of 11		XP_016879991.1
GSDMA	XM_011524651.4	c.179T>C	p.Val60Ala	missense_variant	Exon 3 of 10		XP_011522953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.605T>C	p.Val202Ala	missense_variant	Exon 5 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.605T>C	p.Val202Ala	missense_variant	Exon 5 of 12	5		ENSP00000490739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249218 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135190

Gnomad AFR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461666 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.605T>C (p.V202A) alteration is located in exon 5 (coding exon 4) of the GSDMA gene. This alteration results from a T to C substitution at nucleotide position 605, causing the valine (V) at amino acid position 202 to be replaced by an alanine (A). 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	0.42
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.61	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0070	.;D
Polyphen		0.65	P;P
Vest4		0.49
MutPred		0.69		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.30
MPC		0.21
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.39

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: rs1420777690; hg19: chr17-38127823;