Genetic Variant EDA:p.Arg357Gln (chrX-70035503-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1PM5PP2BP4_ModerateBP6_ModerateBS2

The NM_001399.5(EDA):c.1070G>A(p.Arg357Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,206,739 control chromosomes in the GnomAD database, including 1 homozygotes. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R357W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000051 ( 1 hom. 17 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.94

Publications

3 publications found

Variant links:

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

tooth agenesis, selective, X-linked, 1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
X-linked hypohidrotic ectodermal dysplasia
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EDA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001399.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-70035502-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.

BP4

Computational evidence support a benign effect (MetaRNN=0.15601006).

BP6

Variant X-70035503-G-A is Benign according to our data. Variant chrX-70035503-G-A is described in ClinVar as Benign. ClinVar VariationId is 528362.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 6 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EDA	NM_001399.5	MANE Select	c.1070G>A	p.Arg357Gln	missense	Exon 8 of 8	NP_001390.1
EDA	NM_001005609.2		c.1064G>A	p.Arg355Gln	missense	Exon 8 of 8	NP_001005609.1
EDA	NM_001440761.1		c.1061G>A	p.Arg354Gln	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EDA	ENST00000374552.9	TSL:1 MANE Select	c.1070G>A	p.Arg357Gln	missense	Exon 8 of 8	ENSP00000363680.4
EDA	ENST00000374553.6	TSL:1	c.1064G>A	p.Arg355Gln	missense	Exon 8 of 8	ENSP00000363681.2
EDA	ENST00000524573.5	TSL:1	c.1055G>A	p.Arg352Gln	missense	Exon 8 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes

AF:

0.0000553

AC:

AN:

108523

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00154

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000191

Gnomad OTH

AF:

0.000693

GnomAD2 exomes

AF:

0.0000766

AC:

AN:

182702

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1098216

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

363570

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00175

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30203

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

842132

Other (OTH)

AF:

0.000108

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000553

AC:

AN:

108523

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

30881

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29716

American (AMR)

AF:

0.00

AC:

AN:

9979

Ashkenazi Jewish (ASJ)

AF:

0.00154

AC:

AN:

2602

East Asian (EAS)

AF:

0.00

AC:

AN:

3458

South Asian (SAS)

AF:

0.00

AC:

AN:

2396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

52384

Other (OTH)

AF:

0.000693

AC:

AN:

1442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000217

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Benign:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.16

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

0.69

PhyloP100

4.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.54

Sift

Benign

0.038

Sift4G

Benign

0.31

Polyphen

0.73

Vest4

0.31

MVP

0.98

MPC

1.1

ClinPred

0.18

GERP RS

4.5

Varity_R

0.79

gMVP

0.78

Mutation Taster

=73/27

polymorphism

(source)

Splicing

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

Publications

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over