rs200758965

chr7-24710374-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_001127453.2(GSDME):c.712C>T(p.Arg238Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: GSDME NM_001127453.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.527

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-24710374-G-A is Benign according to our data. Variant chr7-24710374-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228558.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr7-24710374-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.712C>T	p.Arg238Ter	stop_gained	6/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.712C>T	p.Arg238Ter	stop_gained	6/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000525 AC: 132 AN: 251456 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000248 AC XY: 180 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000999 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Arg238X varia nt in DFNA5 has not been previously reported in individuals with hearing loss, b ut has been identified in 0.4% (27/6614) of Finnish chromosomes by the Exome Agg regation consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200758965). T his nonsense variant leads to a premature termination codon at position 238, whi ch is predicted to lead to a truncated or absent protein. However, only variants resulting in altered splicing and skipping of exon 8 have been reported to be c ausative for hearing loss through a gain of function mechanism of disease (Van L aer 2004). The p.Arg238X variant is located in exon 6 of DFNA5 and is expected t o result in loss of function (LoF), which is not a known mechanism of hearing lo ss in this gene. In fact, a frameshift variant in DFNA5 has been reported in mem bers of an Iranian family, in which the variant did not segregate with the heari ng loss (Van Laer 2007). In summary, while the clinical significance of the p.Ar g238X variant is uncertain, its frequency in the Finnish population and the lack of evidence supporting a LoF mechanism for hearing loss in DFNA5 suggests it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.16	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.85
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs200758965; hg19: chr7-24749993; COSMIC: COSV61652169; COSMIC: COSV61652169;