X-70035434-G-C

Variant names:

• chrX-70035434-G-C
• rs142948132
• NM_001399.5:c.1001G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001399.5(EDA):​c.1001G>C​(p.Arg334Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.1001G>C	p.Arg334Pro	missense_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.1001G>C	p.Arg334Pro	missense_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.995G>C	p.Arg332Pro	missense_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.986G>C	p.Arg329Pro	missense_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.605G>C	p.Arg202Pro	missense_variant	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 17, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg334Pro variant in EDA has been identified by our laboratory in 1 male with XLHED and 2 mildly affected females in the same family. It was absent from large population studies. Another change at this position (p.Arg334His) has been reported in one Asian individual with non-syndromic oligodontia and his clinically unaffected m other (consistent with skewed X-inactivation patterns and subclinical phenotypes in females) (Song 2009), but the p.Arg334His variant was also present in 0.9% ( 66/5927, including 9 males) of East Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org, dbSNP rs142948132). While this high frequency in the general population suggests a less likely pathogenic role, the clinical description of individuals included in this database is not provid ed. Thus, it is possible that some of these individuals manifest some features o f HED and that the p.Arg334His variant represents a common pathogenic variant in the East Asian population. Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact of the p.Arg334Pro v ariant to the protein. In summary, while there is some suspicion for a pathogeni c role due to its segregation in affected family members, the clinical significa nce of the p.Arg334Pro variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.6	.;L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N;N;N;.
REVEL	Pathogenic	0.84
Sift	Benign	0.043	D;.;.;.
Sift4G	Benign	0.27	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.64
MutPred		0.75		.;Loss of catalytic residue at R334 (P = 0.0383);.;.;
MVP		1.0
MPC		2.2
ClinPred		0.93	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.99

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;