chrX-70035434-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001399.5(EDA):​c.1001G>A​(p.Arg334His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,207,703 control chromosomes in the GnomAD database, including 4 homozygotes. There are 137 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00065 ( 1 hom., 22 hem., cov: 21)
Exomes 𝑓: 0.00035 ( 3 hom. 115 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

5
7
4

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 9.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a chain Ectodysplasin-A, secreted form (size 231) in uniprot entity EDA_HUMAN there are 42 pathogenic changes around while only 0 benign (100%) in NM_001399.5
BP4
Computational evidence support a benign effect (MetaRNN=0.010842383).
BP6
Variant X-70035434-G-A is Benign according to our data. Variant chrX-70035434-G-A is described in ClinVar as [Benign]. Clinvar id is 253055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70035434-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000654 (72/110131) while in subpopulation EAS AF= 0.0146 (51/3501). AF 95% confidence interval is 0.0114. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 22 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDANM_001399.5 linkc.1001G>A p.Arg334His missense_variant Exon 8 of 8 ENST00000374552.9 NP_001390.1 Q92838-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDAENST00000374552.9 linkc.1001G>A p.Arg334His missense_variant Exon 8 of 8 1 NM_001399.5 ENSP00000363680.4 Q92838-1
EDAENST00000374553.6 linkc.995G>A p.Arg332His missense_variant Exon 8 of 8 1 ENSP00000363681.2 Q92838-3
EDAENST00000524573.5 linkc.986G>A p.Arg329His missense_variant Exon 8 of 8 1 ENSP00000432585.1 Q92838-9
EDAENST00000616899.1 linkc.605G>A p.Arg202His missense_variant Exon 7 of 7 5 ENSP00000481963.1 A0A0C4DGX3

Frequencies

GnomAD3 genomes
AF:
0.000663
AC:
73
AN:
110077
Hom.:
1
Cov.:
21
AF XY:
0.000711
AC XY:
23
AN XY:
32331
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000970
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0148
Gnomad SAS
AF:
0.000396
Gnomad FIN
AF:
0.000345
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000152
Gnomad OTH
AF:
0.000678
GnomAD3 exomes
AF:
0.000920
AC:
166
AN:
180407
Hom.:
2
AF XY:
0.000705
AC XY:
46
AN XY:
65265
show subpopulations
Gnomad AFR exome
AF:
0.000539
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00999
Gnomad SAS exome
AF:
0.000373
Gnomad FIN exome
AF:
0.000253
Gnomad NFE exome
AF:
0.0000500
Gnomad OTH exome
AF:
0.00157
GnomAD4 exome
AF:
0.000354
AC:
389
AN:
1097572
Hom.:
3
Cov.:
31
AF XY:
0.000317
AC XY:
115
AN XY:
362942
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00504
Gnomad4 SAS exome
AF:
0.000444
Gnomad4 FIN exome
AF:
0.000247
Gnomad4 NFE exome
AF:
0.000170
Gnomad4 OTH exome
AF:
0.00119
GnomAD4 genome
AF:
0.000654
AC:
72
AN:
110131
Hom.:
1
Cov.:
21
AF XY:
0.000679
AC XY:
22
AN XY:
32395
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.0000969
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0146
Gnomad4 SAS
AF:
0.000397
Gnomad4 FIN
AF:
0.000345
Gnomad4 NFE
AF:
0.000152
Gnomad4 OTH
AF:
0.000669
Alfa
AF:
0.000294
Hom.:
7
Bravo
AF:
0.000491
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000522
AC:
2
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.000692
AC:
84

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EDA: BS1, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Tooth agenesis, selective, X-linked, 1 Pathogenic:1Benign:1
Aug 17, 2016
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: curation

NM_001399.4:c.1001G>A in EDA gene has an allele frequency of 0.011 in East Asian subpopulation in the gnomAD database, including 2 homozygous occurrences, and 54 hemizygotes. This variant was reported in a male patient with Non-syndromic Oligodontia, inherited from his mother, which indicated a X-linked recessive inheritance (PMID: 19278982). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

Hypohidrotic X-linked ectodermal dysplasia Benign:2
Jul 23, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 Benign:1
Nov 05, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Benign:1
Feb 17, 2020
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
.;D;.;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
MetaRNN
Benign
0.011
T;T;T;T
MetaSVM
Uncertain
0.74
D
MutationAssessor
Benign
1.2
.;L;.;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.3
N;N;N;.
REVEL
Pathogenic
0.77
Sift
Uncertain
0.025
D;.;.;.
Sift4G
Uncertain
0.044
D;T;D;T
Polyphen
1.0
D;D;D;.
Vest4
0.26
MVP
1.0
MPC
1.5
ClinPred
0.058
T
GERP RS
5.5
Varity_R
0.89
gMVP
0.86

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142948132; hg19: chrX-69255284; API