8-143560761-C-T

Variant names:

• chr8-143560761-C-T
• rs540292430
• NM_024736.7:c.569C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024736.7(GSDMD):​c.569C>T​(p.Thr190Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 1,546,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T190K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: GSDMD NM_024736.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031035662).

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.569C>T	p.Thr190Met	missense	Exon 4 of 11	NP_079012.3
	GSDMD	NM_001166237.1		c.569C>T	p.Thr190Met	missense	Exon 7 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.569C>T	p.Thr190Met	missense	Exon 4 of 11	ENSP00000262580.4	P57764
	GSDMD	ENST00000533063.5	TSL:1	c.713C>T	p.Thr238Met	missense	Exon 5 of 12	ENSP00000433958.1	G3V1A6
	GSDMD	ENST00000526406.5	TSL:2	c.569C>T	p.Thr190Met	missense	Exon 7 of 14	ENSP00000433209.1	P57764

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000342 AC: 5 AN: 146286 AF XY: 0.0000637

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000836

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000891

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000380 AC: 53 AN: 1394546 Hom.: 0 Cov.: 35 AF XY: 0.0000349 AC XY: 24 AN XY: 687926

African (AFR) AF: 0.0000628 AC: 2 AN: 31838

American (AMR) AF: 0.0000850 AC: 3 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24492

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36166

South Asian (SAS) AF: 0.00 AC: 0 AN: 78724

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5254

European-Non Finnish (NFE) AF: 0.0000371 AC: 40 AN: 1077306

Other (OTH) AF: 0.000104 AC: 6 AN: 57692

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152312 Hom.: 0 Cov.: 35 AF XY: 0.0000537 AC XY: 4 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000392 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.86
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00098	N
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.35
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.87	N
REVEL	Benign	0.010
Sift	Benign	0.43	T
Sift4G	Benign	0.56	T
Polyphen		0.031	B
Vest4		0.082
MutPred		0.43		Loss of glycosylation at T238 (P = 0.0264)
MVP		0.048
MPC		0.14
ClinPred		0.021	T
GERP RS		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.0095
gMVP		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs540292430; hg19: chr8-144642931;