rs754554

Variant names:

• chr7-24719199-G-A
• rs754554
• NM_001127453.2:c.424C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-24719199-G-A
• chr7-24719199-G-C
• chr7-24719199-G-T

Variant summary

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

The NM_001127453.2(GSDME):​c.424C>T​(p.Pro142Ser) 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. 14/23 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. P142A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.943
• Publications: 42 publications found

Genes affected

GSDME (HGNC:2810): (gasdermin E) Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GSDME Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.424C>T	p.Pro142Ser	missense_variant	Exon 4 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.424C>T	p.Pro142Ser	missense_variant	Exon 4 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.54
DEOGEN2	Benign	0.047	T;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.69	.;.;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-0.96	T
PhyloP100		0.94
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;.;N;.
REVEL	Benign	0.026
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.27	B;B;B;.
Vest4		0.083
MutPred		0.40		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.17
MPC		0.039
ClinPred		0.13	T
GERP RS		0.25
PromoterAI		-0.023	Neutral
Varity_R		0.033
gMVP		0.27
Mutation Taster		=292/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -12

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

Other links and lift over

dbSNP: rs754554; hg19: chr7-24758818;