rs121908116

Positions:

• chr1-236482366-T-A
• chr1-236482366-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_145861.4(EDARADD):​c.365T>A​(p.Leu122Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L122R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_145861.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-236482366-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4189.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDARADD	NM_145861.4	c.365T>A	p.Leu122Gln	missense_variant	6/6	ENST00000334232.9
EDARADD	NM_080738.4	c.335T>A	p.Leu112Gln	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDARADD	ENST00000334232.9	c.365T>A	p.Leu122Gln	missense_variant	6/6	1	NM_145861.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;D;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.1	.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	.;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.95, 0.89
MutPred		0.77		.;Gain of solvent accessibility (P = 0.0137);.;
MVP		0.95
MPC		1.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-236645666;