rs777408599

Variant names:

• chr7-24717264-G-GT
• rs777408599
• NM_001127453.2:c.686dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001127453.2(GSDME):​c.686dupA​(p.Asp229GlufsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,579,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D229D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GSDME NM_001127453.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.01
• Publications: 0 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):

• nonsyndromic genetic hearing loss

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-24717264-G-GT is Benign according to our data. Variant chr7-24717264-G-GT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517170.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000451 (6/132908) while in subpopulation AMR AF = 0.000491 (6/12228). AF 95% confidence interval is 0.000213. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127453.2. 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
	GSDME	NM_001127453.2	MANE Select	c.686dupA	p.Asp229GlufsTer23	frameshift	Exon 5 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.686dupA	p.Asp229GlufsTer23	frameshift	Exon 5 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.194dupA	p.Asp65GlufsTer23	frameshift	Exon 4 of 9	NP_001120926.1	O60443-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.686dupA	p.Asp229GlufsTer23	frameshift	Exon 5 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.686dupA	p.Asp229GlufsTer23	frameshift	Exon 5 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.194dupA	p.Asp65GlufsTer23	frameshift	Exon 4 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0000451 AC: 6 AN: 132908 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250602 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1446864 Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9 AN XY: 719396

African (AFR) AF: 0.00 AC: 0 AN: 33288

American (AMR) AF: 0.000251 AC: 11 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.00 AC: 0 AN: 38352

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51958

Middle Eastern (MID) AF: 0.000580 AC: 3 AN: 5168

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104218

Other (OTH) AF: 0.0000168 AC: 1 AN: 59548

GnomAD4 genome AF: 0.0000451 AC: 6 AN: 132908 Hom.: 0 Cov.: 31 AF XY: 0.0000932 AC XY: 6 AN XY: 64344

African (AFR) AF: 0.00 AC: 0 AN: 38028

American (AMR) AF: 0.000491 AC: 6 AN: 12228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2980

East Asian (EAS) AF: 0.00 AC: 0 AN: 4342

South Asian (SAS) AF: 0.00 AC: 0 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59786

Other (OTH) AF: 0.00 AC: 0 AN: 1820

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000945

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=16/184	disease causing (fs/PTC)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs777408599;

hg19: chr7-24756883;