17-39972607-G-T

Position:

• chr17-39972607-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_178171.5(GSDMA):​c.724G>T​(p.Val242Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,612,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: GSDMA NM_178171.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.495

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013776332).
• BP6: Variant 17-39972607-G-T is Benign according to our data. Variant chr17-39972607-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3102799.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMA	NM_178171.5	c.724G>T	p.Val242Phe	missense_variant	7/12	ENST00000301659.9	NP_835465.2
GSDMA	XM_006721832.4	c.724G>T	p.Val242Phe	missense_variant	7/12		XP_006721895.1
GSDMA	XM_011524651.4	c.298G>T	p.Val100Phe	missense_variant	5/10		XP_011522953.1
GSDMA	XM_017024502.3	c.703+431G>T		intron_variant			XP_016879991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDMA	ENST00000301659.9	c.724G>T	p.Val242Phe	missense_variant	7/12	1	NM_178171.5	ENSP00000301659.4
GSDMA	ENST00000635792.1	c.724G>T	p.Val242Phe	missense_variant	7/12	5		ENSP00000490739.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000850 AC: 21 AN: 246988 Hom.: 0 AF XY: 0.0000971 AC XY: 13 AN XY: 133816

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000589 AC: 86 AN: 1460300 Hom.: 1 Cov.: 31 AF XY: 0.0000606 AC XY: 44 AN XY: 726250

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.000996

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.4
DANN	Benign	0.74
DEOGEN2	Benign	0.0036	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.38	.;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.16	.;N
REVEL	Benign	0.043
Sift	Benign	0.53	.;T
Sift4G	Benign	0.61	.;T
Polyphen		0.0	B;B
Vest4		0.14
MVP		0.14
MPC		0.094
ClinPred		0.0099	T
GERP RS		-2.4
Varity_R		0.051
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs187128895; hg19: chr17-38128860;