rs146567337

chr2-108897116-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022336.4(EDAR):c.1138A>C(p.Ser380Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,614,018 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (18 hom.)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 7.67

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_022336.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009544849).
• BP6: Variant 2-108897116-T-G is Benign according to our data. Variant chr2-108897116-T-G is described in ClinVar as [Benign]. Clinvar id is 261571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108897116-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000953 (145/152196) while in subpopulation EAS AF= 0.0244 (126/5166). AF 95% confidence interval is 0.0209. There are 3 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.1138A>C	p.Ser380Arg	missense_variant	12/12	ENST00000258443.7
EDAR	XM_006712204.2	c.1234A>C	p.Ser412Arg	missense_variant	11/11
RANBP2	XM_047445367.1	c.8370+124070T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.1138A>C	p.Ser380Arg	missense_variant	12/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.1234A>C	p.Ser412Arg	missense_variant	11/11	2
EDAR	ENST00000409271.5	c.1234A>C	p.Ser412Arg	missense_variant	12/12	2

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152078 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00185 AC: 464 AN: 250168 Hom.: 13 AF XY: 0.00170 AC XY: 230 AN XY: 135318

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0236

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000789 AC: 1153 AN: 1461822 Hom.: 18 Cov.: 38 AF XY: 0.000741 AC XY: 539 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0240

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.000953 AC: 145 AN: 152196 Hom.: 3 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74402

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0244

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00115 Hom.: 3

Bravo AF: 0.00102

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-syndromic oligodontia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Prosthodontics, Peking University School and Hospital of Stomatology

Apr 27, 2020

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hypohidrotic ectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Uncertain	0.062	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.60
MutPred		0.63		.;Gain of MoRF binding (P = 0.017);.;
MVP		0.96
MPC		1.1
ClinPred		0.046	T
GERP RS		5.6
Varity_R		0.54
gMVP		0.93

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: rs146567337; hg19: chr2-109513572;