dbSNP rs397516654: EDA:p.Val365Ala (chrX-70035527-T-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 13P and 4B. PM1PM5PP2PP5_Very_StrongBS2

The NM_001399.5(EDA):c.1094T>C(p.Val365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000431 in 1,205,588 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V365M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000045 ( 0 hom. 13 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.35

Publications

2 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, Labcorp Genetics (formerly Invitae), Orphanet
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_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001399.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-70035526-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1482275.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.

PP5

Variant X-70035527-T-C is Pathogenic according to our data. Variant chrX-70035527-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 49 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	UniProt
EDA	NM_001399.5	MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	NP_001390.1	Q92838-1
EDA	NM_001005609.2		c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	NP_001005609.1	Q92838-3
EDA	NM_001440761.1		c.1085T>C	p.Val362Ala	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDA	ENST00000374552.9	TSL:1 MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	ENSP00000363680.4	Q92838-1
EDA	ENST00000374553.6	TSL:1	c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	ENSP00000363681.2	Q92838-3
EDA	ENST00000524573.5	TSL:1	c.1079T>C	p.Val360Ala	missense	Exon 8 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

107573

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000575

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182595

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1098015

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363371

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

841954

Other (OTH)

AF:

0.0000217

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000279

AC:

AN:

107573

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

29983

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29419

American (AMR)

AF:

0.00

AC:

AN:

9807

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2581

East Asian (EAS)

AF:

0.00

AC:

AN:

3420

South Asian (SAS)

AF:

0.00

AC:

AN:

2349

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000575

AC:

AN:

52170

Other (OTH)

AF:

0.00

AC:

AN:

1422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

EDA-related disorder (1)

Hypodontia (1)

Hypohidrotic X-linked ectodermal dysplasia (2)

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)

Inborn genetic diseases (1)

not provided (1)

Tooth agenesis, selective, X-linked, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.45

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.35

PhyloP100

4.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.52

REVEL

Pathogenic

0.67

Sift

Benign

0.047

Sift4G

Benign

0.087

Polyphen

0.39

Vest4

0.16

MVP

1.0

MPC

1.1

ClinPred

0.46

GERP RS

5.4

Varity_R

0.83

gMVP

0.89

Mutation Taster

=32/68

disease causing (ClinVar)

(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

Computational scores

Splicing

Publications

Other links and lift over