rs28407350

chr2-108930237-A-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_022336.4(EDAR):c.57T>A(p.Ser19=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,074 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 0.0072 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: EDAR NM_022336.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.21

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-108930237-A-T is Benign according to our data. Variant chr2-108930237-A-T is described in ClinVar as [Benign]. Clinvar id is 532548.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-108930237-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00718 (1093/152290) while in subpopulation AFR AF= 0.0255 (1058/41542). AF 95% confidence interval is 0.0242. There are 10 homozygotes in gnomad4. There are 532 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDAR	NM_022336.4	c.57T>A	p.Ser19=	synonymous_variant	3/12	ENST00000258443.7
EDAR	XM_006712204.2	c.57T>A	p.Ser19=	synonymous_variant	3/11
RANBP2	XM_047445367.1	c.8370+157191A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDAR	ENST00000258443.7	c.57T>A	p.Ser19=	synonymous_variant	3/12	1	NM_022336.4	P1
EDAR	ENST00000376651.1	c.57T>A	p.Ser19=	synonymous_variant	3/11	2
EDAR	ENST00000409271.5	c.57T>A	p.Ser19=	synonymous_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 1078 AN: 152172 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00189 AC: 475 AN: 251332 Hom.: 3 AF XY: 0.00147 AC XY: 200 AN XY: 135878

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00136

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: 0.0000616

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000750 AC: 1097 AN: 1461784 Hom.: 11 Cov.: 31 AF XY: 0.000686 AC XY: 499 AN XY: 727196

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00718 AC: 1093 AN: 152290 Hom.: 10 Cov.: 33 AF XY: 0.00714 AC XY: 532 AN XY: 74484

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00237 Hom.: 1

Bravo AF: 0.00824

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 24, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.60
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28407350; hg19: chr2-109546693;