1-236482510-G-T

Variant names:

• chr1-236482510-G-T
• NM_145861.4:c.509G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_145861.4(EDARADD):​c.509G>T​(p.Arg170Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R170Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EDARADD NM_145861.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 6 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, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDARADD	NM_145861.4	c.509G>T	p.Arg170Leu	missense_variant	Exon 6 of 6	ENST00000334232.9	NP_665860.2
EDARADD	NM_080738.5	c.479G>T	p.Arg160Leu	missense_variant	Exon 6 of 6		NP_542776.1
EDARADD	NM_001422628.1	c.443G>T	p.Arg148Leu	missense_variant	Exon 8 of 8		NP_001409557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDARADD	ENST00000334232.9	c.509G>T	p.Arg170Leu	missense_variant	Exon 6 of 6	1	NM_145861.4	ENSP00000335076.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	.;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.93, 0.87
MutPred		0.71		.;Loss of MoRF binding (P = 0.0094);.;
MVP		0.90
MPC		1.8
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.74

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: chr1-236645810;