X-70035434-G-T

Position:

• chrX-70035434-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001399.5(EDA):​c.1001G>T​(p.Arg334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.1001G>T	p.Arg334Leu	missense_variant	8/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.1001G>T	p.Arg334Leu	missense_variant	8/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.995G>T	p.Arg332Leu	missense_variant	8/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.986G>T	p.Arg329Leu	missense_variant	8/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.605G>T	p.Arg202Leu	missense_variant	7/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000554 AC: 1 AN: 180407 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097573 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362943

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.2	.;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N;N;N;.
REVEL	Pathogenic	0.79
Sift	Benign	0.040	D;.;.;.
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.98	D;D;D;.
Vest4		0.56
MutPred		0.77		.;Gain of catalytic residue at Q331 (P = 0.0449);.;.;
MVP		0.98
MPC		1.5
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.94

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; COSMIC: COSV100999898; COSMIC: COSV100999898;