rs876657687

Variant names:

• chrX-70035393-T-C
• rs876657687
• NM_001399.5:c.960T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-70035393-T-C
• chrX-70035393-T-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001399.5(EDA):​c.960T>C​(p.Tyr320Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,206,830 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: EDA NM_001399.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.527
• Publications: 1 publications found

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-70035393-T-C is Benign according to our data. Variant chrX-70035393-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2729786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.527 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.960T>C	p.Tyr320Tyr	synonymous_variant	Exon 8 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.960T>C	p.Tyr320Tyr	synonymous_variant	Exon 8 of 8	1	NM_001399.5	ENSP00000363680.4
EDA	ENST00000374553.6	c.954T>C	p.Tyr318Tyr	synonymous_variant	Exon 8 of 8	1		ENSP00000363681.2
EDA	ENST00000524573.5	c.945T>C	p.Tyr315Tyr	synonymous_variant	Exon 8 of 8	1		ENSP00000432585.1
EDA	ENST00000616899.1	c.564T>C	p.Tyr188Tyr	synonymous_variant	Exon 7 of 7	5		ENSP00000481963.1

Frequencies

GnomAD3 genomes AF: 0.00000908 AC: 1 AN: 110103 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096727 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 2 AN XY: 362171

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26381

American (AMR) AF: 0.00 AC: 0 AN: 35082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19338

East Asian (EAS) AF: 0.00 AC: 0 AN: 30174

South Asian (SAS) AF: 0.00 AC: 0 AN: 53815

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40437

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841311

Other (OTH) AF: 0.0000217 AC: 1 AN: 46057

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000908 AC: 1 AN: 110103 Hom.: 0 Cov.: 21 AF XY: 0.0000309 AC XY: 1 AN XY: 32341

African (AFR) AF: 0.00 AC: 0 AN: 30216

American (AMR) AF: 0.00 AC: 0 AN: 10282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2626

East Asian (EAS) AF: 0.00 AC: 0 AN: 3488

South Asian (SAS) AF: 0.00 AC: 0 AN: 2493

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5849

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000190 AC: 1 AN: 52755

Other (OTH) AF: 0.00 AC: 0 AN: 1476

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Benign:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.3
DANN	Benign	0.45
PhyloP100		-0.53

Splicing

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

Other links and lift over

dbSNP: rs876657687; hg19: chrX-69255243;