Genetic Variant GSDME:p.Phe445Tyr (chr7-24699183-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127453.2(GSDME):c.1334T>A(p.Phe445Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000893 in 1,614,164 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 21 hom. )

Consequence

GSDME
NM_001127453.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.24

Publications

2 publications found

Variant links:

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

GSDME links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005707741).

BP6

Variant 7-24699183-A-T is Benign according to our data. Variant chr7-24699183-A-T is described in ClinVar as Benign. ClinVar VariationId is 44841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00144 (219/152278) while in subpopulation AMR AF = 0.0114 (174/15296). AF 95% confidence interval is 0.00999. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 219 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	NM_001127453.2	MANE Select	c.1334T>A	p.Phe445Tyr	missense	Exon 10 of 10	NP_001120925.1
GSDME	NM_004403.3		c.1334T>A	p.Phe445Tyr	missense	Exon 10 of 10	NP_004394.1
GSDME	NM_001127454.2		c.842T>A	p.Phe281Tyr	missense	Exon 9 of 9	NP_001120926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	ENST00000645220.1	MANE Select	c.1334T>A	p.Phe445Tyr	missense	Exon 10 of 10	ENSP00000494186.1
GSDME	ENST00000342947.9	TSL:1	c.1334T>A	p.Phe445Tyr	missense	Exon 10 of 10	ENSP00000339587.3
GSDME	ENST00000419307.6	TSL:1	c.842T>A	p.Phe281Tyr	missense	Exon 9 of 9	ENSP00000401332.1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

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:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00381

AC:

957

AN:

251454

AF XY:

0.00265

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0265

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.000837

AC:

1223

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

490

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.0253

AC:

1132

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1112006

Other (OTH)

AF:

0.000894

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00144

AC:

219

AN:

152278

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41554

American (AMR)

AF:

0.0114

AC:

174

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.00254

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00284

AC:

345

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Autosomal dominant nonsyndromic hearing loss 5 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0057

MetaSVM

Uncertain

0.11

PhyloP100

5.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.61

Sift

Benign

0.12

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.51

MVP

0.60

MPC

0.28

ClinPred

0.030

GERP RS

5.6

Varity_R

0.12

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over