rs142948132

chrX-70035434-G-AchrX-70035434-G-CchrX-70035434-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334C) has been classified 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 9.25

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain 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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.1001G>A	p.Arg334His	missense_variant	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.1001G>A	p.Arg334His	missense_variant	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.995G>A	p.Arg332His	missense_variant	8/8	1		A1
EDA	ENST00000524573.5	c.986G>A	p.Arg329His	missense_variant	8/8	1		A1
EDA	ENST00000616899.1	c.605G>A	p.Arg202His	missense_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 73 AN: 110077 Hom.: 1 Cov.: 21 AF XY: 0.000711 AC XY: 23 AN XY: 32331

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

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

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

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:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EDA: BS1, BS2 -

Tooth agenesis, selective, X-linked, 1 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 17, 2016	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

See cases Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 17, 2020

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
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
MutationTaster	Benign	1.0	D;D;D
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

Other links and lift over

dbSNP: rs142948132; hg19: chrX-69255284;