chr17-39974920-G-C

Position:

• chr17-39974920-G-C

Variant summary

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

The NM_178171.5(GSDMA):​c.927G>C​(p.Lys309Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,632 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.

• 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: 0.995

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=0.24184647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.927G>C	p.Lys309Asn	missense_variant	10/12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.927G>C	p.Lys309Asn	missense_variant	10/12		XP_006721895.1
GSDMA	XM_017024502.3	c.900G>C	p.Lys300Asn	missense_variant	9/11		XP_016879991.1
GSDMA	XM_011524651.4	c.501G>C	p.Lys167Asn	missense_variant	8/10		XP_011522953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.927G>C	p.Lys309Asn	missense_variant	10/12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.927G>C	p.Lys309Asn	missense_variant	10/12	5		ENSP00000490739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456632 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724746

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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

Jul 27, 2024

The c.927G>C (p.K309N) alteration is located in exon 10 (coding exon 9) of the GSDMA gene. This alteration results from a G to C substitution at nucleotide position 927, causing the lysine (K) at amino acid position 309 to be replaced by an asparagine (N). 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	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0049	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.42	.;N
REVEL	Benign	0.14
Sift	Benign	0.74	.;T
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.39
MutPred		0.47		Loss of solvent accessibility (P = 7e-04);Loss of solvent accessibility (P = 7e-04);
MVP		0.31
MPC		0.39
ClinPred		0.94	D
GERP RS		2.9
Varity_R		0.053
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs776190104; hg19: chr17-38131173;