chr7-24710374-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BP6BS2
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
NM_001127453.2 stop_gained
Scores
1
3
3
Clinical Significance
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
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: 45AN: 152184Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
45
AN:
152184
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000525 AC: 132AN: 251456Hom.: 0 AF XY: 0.000537 AC XY: 73AN XY: 135914
GnomAD3 exomes
AF:
AC:
132
AN:
251456
Hom.:
AF XY:
AC XY:
73
AN XY:
135914
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000254 AC: 371AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.000248 AC XY: 180AN XY: 727238
GnomAD4 exome
AF:
AC:
371
AN:
1461880
Hom.:
Cov.:
31
AF XY:
AC XY:
180
AN XY:
727238
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000296 AC: 45AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74342
GnomAD4 genome
?
AF:
AC:
45
AN:
152184
Hom.:
Cov.:
32
AF XY:
AC XY:
35
AN XY:
74342
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
0
ExAC
?
AF:
AC:
43
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign: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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at