17-39966406-G-T

Position:

• chr17-39966406-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178171.5(GSDMA):​c.361G>T​(p.Ala121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.623

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12776014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.361G>T	p.Ala121Ser	missense_variant	3/12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.361G>T	p.Ala121Ser	missense_variant	3/12		XP_006721895.1
GSDMA	XM_017024502.3	c.361G>T	p.Ala121Ser	missense_variant	3/11		XP_016879991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.361G>T	p.Ala121Ser	missense_variant	3/12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.361G>T	p.Ala121Ser	missense_variant	3/12	5		ENSP00000490739.1
GSDMA	ENST00000577447.1	c.361G>T	p.Ala121Ser	missense_variant	3/4	4		ENSP00000461985.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.361G>T (p.A121S) alteration is located in exon 3 (coding exon 2) of the GSDMA gene. This alteration results from a G to T substitution at nucleotide position 361, causing the alanine (A) at amino acid position 121 to be replaced by a serine (S). 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	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.0019	T;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.64	.;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.35	.;N;.
REVEL	Benign	0.027
Sift	Benign	0.53	.;T;.
Sift4G	Benign	0.36	.;T;T
Polyphen		0.0010	B;B;.
Vest4		0.068
MutPred		0.40		Gain of disorder (P = 0.0331);Gain of disorder (P = 0.0331);Gain of disorder (P = 0.0331);
MVP		0.092
MPC		0.067
ClinPred		0.34	T
GERP RS		0.28
Varity_R		0.059
gMVP		0.099

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38122659; COSMIC: COSV100053820;