17-39965740-G-C

Variant names:

• chr17-39965740-G-C
• NM_178171.5:c.53G>C

Variant summary

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

The NM_178171.5(GSDMA):​c.53G>C​(p.Arg18Pro) 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 1,458,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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=0.28306556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 12		XP_006721895.1
GSDMA	XM_017024502.3	c.53G>C	p.Arg18Pro	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.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 12	5		ENSP00000490739.1
GSDMA	ENST00000577447.1	c.53G>C	p.Arg18Pro	missense_variant	Exon 2 of 4	4		ENSP00000461985.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458410 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 725170

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.038	T;T;T
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	.;D;.
REVEL	Benign	0.14
Sift	Benign	0.036	.;D;.
Sift4G	Uncertain	0.0090	.;D;D
Polyphen		0.52	P;P;.
Vest4		0.41
MutPred		0.42		Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);Loss of solvent accessibility (P = 0.0111);
MVP		0.35
MPC		0.11
ClinPred		0.60	D
GERP RS		3.3
Varity_R		0.44
gMVP		0.58

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: chr17-38121993; COSMIC: COSV56975402;