rs61747506

chrX-70035503-G-AchrX-70035503-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PM5 BP4_Moderate BP6_Moderate BS2

The NM_001399.5(EDA):c.1070G>A(p.Arg357Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,206,739 control chromosomes in the GnomAD database, including 1 homozygotes. There are 18 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. R357W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000051 (1 hom. 17 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.94

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001399.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70035502-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15601006).
• BP6: Variant X-70035503-G-A is Benign according to our data. Variant chrX-70035503-G-A is described in ClinVar as [Benign]. Clinvar id is 528362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.1070G>A	p.Arg357Gln	missense_variant	8/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.1070G>A	p.Arg357Gln	missense_variant	8/8	1	NM_001399.5	P4
EDA	ENST00000374553.6	c.1064G>A	p.Arg355Gln	missense_variant	8/8	1		A1
EDA	ENST00000524573.5	c.1055G>A	p.Arg352Gln	missense_variant	8/8	1		A1
EDA	ENST00000616899.1	c.674G>A	p.Arg225Gln	missense_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.0000553 AC: 6 AN: 108523 Hom.: 0 Cov.: 21 AF XY: 0.0000324 AC XY: 1 AN XY: 30881

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00154

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000191

Gnomad OTH AF: 0.000693

GnomAD3 exomes AF: 0.0000766 AC: 14 AN: 182702 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000510 AC: 56 AN: 1098216 Hom.: 1 Cov.: 31 AF XY: 0.0000468 AC XY: 17 AN XY: 363570

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00175

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.000108

GnomAD4 genome AF: 0.0000553 AC: 6 AN: 108523 Hom.: 0 Cov.: 21 AF XY: 0.0000324 AC XY: 1 AN XY: 30881

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00154

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000191

Gnomad4 OTH AF: 0.000693

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.56	N;N;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.038	D;.;.;.
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.73	P;P;P;.
Vest4		0.31
MVP		0.98
MPC		1.1
ClinPred		0.18	T
GERP RS		4.5
Varity_R		0.79
gMVP		0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61747506; hg19: chrX-69255353;