17-39965705-T-A

Variant names:

• chr17-39965705-T-A
• NM_178171.5:c.18T>A

Variant summary

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

The NM_178171.5(GSDMA):​c.18T>A​(p.Asn6Lys) 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 1,455,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.727

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=0.18396601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 11		XP_016879991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 12	5		ENSP00000490739.1
GSDMA	ENST00000577447.1	c.18T>A	p.Asn6Lys	missense_variant	Exon 2 of 4	4		ENSP00000461985.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455422 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723392

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.18T>A (p.N6K) alteration is located in exon 2 (coding exon 1) of the GSDMA gene. This alteration results from a T to A substitution at nucleotide position 18, causing the asparagine (N) at amino acid position 6 to be replaced by a lysine (K). 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	0.25
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.0020	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.57	.;N;.
REVEL	Benign	0.059
Sift	Benign	0.15	.;T;.
Sift4G	Uncertain	0.035	.;D;T
Polyphen		0.80	P;P;.
Vest4		0.64
MutPred		0.50		Gain of MoRF binding (P = 0.0068);Gain of MoRF binding (P = 0.0068);Gain of MoRF binding (P = 0.0068);
MVP		0.12
MPC		0.40
ClinPred		0.51	D
GERP RS		1.8
Varity_R		0.060
gMVP		0.36

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: chr17-38121958;