rs74315309

chr1-236482455-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_145861.4(EDARADD):c.454G>A(p.Glu152Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.37

Genes affected

EDARADD (HGNC:14341): (EDAR associated via death domain) This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Death (size 79) in uniprot entity EDAD_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_145861.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 1-236482455-G-A is Pathogenic according to our data. Variant chr1-236482455-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4188.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-236482455-G-A is described in Lovd as [Pathogenic]. Variant chr1-236482455-G-A is described in Lovd as [Pathogenic]. Variant chr1-236482455-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.454G>A	p.Glu152Lys	missense_variant	6/6	ENST00000334232.9
EDARADD	NM_080738.4	c.424G>A	p.Glu142Lys	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.454G>A	p.Glu152Lys	missense_variant	6/6	1	NM_145861.4
EDARADD	ENST00000359362.6	c.424G>A	p.Glu142Lys	missense_variant	6/6	1		P1
EDARADD	ENST00000637660.1	c.388G>A	p.Glu130Lys	missense_variant	6/6	5
EDARADD	ENST00000642595.1	c.236-9282G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251302 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000163

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2007

- -

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	T
Polyphen		1.0	.;D;.
Vest4		0.94, 0.90
MutPred		0.92		.;Gain of MoRF binding (P = 0.0141);.;
MVP		0.93
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.59
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315309; hg19: chr1-236645755; COSMIC: COSV100512683; COSMIC: COSV100512683;