17-39970544-T-A

Variant names:

• chr17-39970544-T-A
• NM_178171.5:c.455T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178171.5(GSDMA):​c.455T>A​(p.Val152Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 11		XP_016879991.1
GSDMA	XM_011524651.4	c.29T>A	p.Val10Glu	missense_variant	Exon 2 of 10		XP_011522953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 12	5		ENSP00000490739.1
GSDMA	ENST00000577447.1	c.455T>A	p.Val152Glu	missense_variant	Exon 4 of 4	4		ENSP00000461985.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456330 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Oct 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.455T>A (p.V152E) alteration is located in exon 4 (coding exon 3) of the GSDMA gene. This alteration results from a T to A substitution at nucleotide position 455, causing the valine (V) at amino acid position 152 to be replaced by a glutamic acid (E). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	.;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.83		Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);
MVP		0.47
MPC		0.49
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 1

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: chr17-38126797;