8-143559541-C-G

Position:

• chr8-143559541-C-G

Variant summary

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

The NM_024736.7(GSDMD):​c.206C>G​(p.Ala69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSDMD NM_024736.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.257

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]

GSDMD (HGNC:):

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=0.13120952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDMD	NM_024736.7	c.206C>G	p.Ala69Gly	missense_variant	2/11	ENST00000262580.9	NP_079012.3
GSDMD	NM_001166237.1	c.206C>G	p.Ala69Gly	missense_variant	5/14		NP_001159709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDMD	ENST00000262580.9	c.206C>G	p.Ala69Gly	missense_variant	2/11	1	NM_024736.7	ENSP00000262580.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Feb 27, 2023

The c.206C>G (p.A69G) alteration is located in exon 5 (coding exon 1) of the GSDMD gene. This alteration results from a C to G substitution at nucleotide position 206, causing the alanine (A) at amino acid position 69 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;T;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D
REVEL	Benign	0.050
Sift	Uncertain	0.020	D;D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.96	D;.;D;D;.;.;.
Vest4		0.076
MutPred		0.44		.;.;Gain of disorder (P = 0.107);.;.;.;.;
MVP		0.15
MPC		0.21
ClinPred		0.48	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.10

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: chr8-144641711;