rs770774804

Variant names:

• chr8-143559343-C-T
• rs770774804
• NM_024736.7:c.8C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024736.7(GSDMD):​c.8C>T​(p.Ser3Leu) 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 1,355,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: GSDMD NM_024736.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.803
• Publications: 1 publications found

Genes affected

GSDMD (HGNC:25697): (gasdermin D) Gasdermin D is a member of the gasdermin family. Members of this family appear to play a role in regulation of epithelial proliferation. Gasdermin D has been suggested to act as a tumor suppressor. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024736.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDMD	NM_024736.7	MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 2 of 11	NP_079012.3
	GSDMD	NM_001166237.1		c.8C>T	p.Ser3Leu	missense	Exon 5 of 14	NP_001159709.1	P57764

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDMD	ENST00000262580.9	TSL:1 MANE Select	c.8C>T	p.Ser3Leu	missense	Exon 2 of 11	ENSP00000262580.4	P57764
	GSDMD	ENST00000533063.5	TSL:1	c.152C>T	p.Ser51Leu	missense	Exon 3 of 12	ENSP00000433958.1	G3V1A6
	GSDMD	ENST00000526406.5	TSL:2	c.8C>T	p.Ser3Leu	missense	Exon 5 of 14	ENSP00000433209.1	P57764

Frequencies

GnomAD3 genomes AF: 0.0000142 AC: 2 AN: 140950 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248578 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 88 AN: 1214388 Hom.: 0 Cov.: 35 AF XY: 0.0000648 AC XY: 39 AN XY: 601434

African (AFR) AF: 0.00 AC: 0 AN: 26976

American (AMR) AF: 0.00 AC: 0 AN: 37316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16824

East Asian (EAS) AF: 0.00 AC: 0 AN: 16766

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4470

European-Non Finnish (NFE) AF: 0.0000913 AC: 87 AN: 952776

Other (OTH) AF: 0.00 AC: 0 AN: 44134

GnomAD4 genome AF: 0.0000142 AC: 2 AN: 140950 Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 1 AN XY: 68296

African (AFR) AF: 0.0000255 AC: 1 AN: 39238

American (AMR) AF: 0.00 AC: 0 AN: 14278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.00 AC: 0 AN: 4024

South Asian (SAS) AF: 0.00 AC: 0 AN: 3808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64378

Other (OTH) AF: 0.00 AC: 0 AN: 1994

Alfa AF: 0.0000565 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.0098
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.80
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.31		Loss of phosphorylation at S51 (P = 0.0333)
MVP		0.58
MPC		0.58
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.57
gMVP		0.41
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770774804; hg19: chr8-144641513;