X-69616368-A-C

Variant names:

• chrX-69616368-A-C
• rs183801635
• NM_001399.5:c.60A>C

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.60A>C​(p.Arg20Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,206,729 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 133 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00032 (0 hom. 113 hem.)
• Consequence: EDA NM_001399.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0230
• Publications: 0 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=-0.88).
• BP6: Variant X-69616368-A-C is Benign according to our data. Variant chrX-69616368-A-C is described in ClinVar as [Benign]. Clinvar id is 1169967.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.
• BS2: High AC in GnomAd4 at 34 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.60A>C	p.Arg20Arg	synonymous_variant	Exon 1 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.60A>C	p.Arg20Arg	synonymous_variant	Exon 1 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 34 AN: 112733 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000440 AC: 76 AN: 172715 AF XY: 0.000339

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000318 AC: 348 AN: 1093937 Hom.: 0 Cov.: 31 AF XY: 0.000313 AC XY: 113 AN XY: 360963

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35105

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19288

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 53955

European-Finnish (FIN) AF: 0.00343 AC: 130 AN: 37904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3863

European-Non Finnish (NFE) AF: 0.000252 AC: 212 AN: 841346

Other (OTH) AF: 0.000109 AC: 5 AN: 45943

GnomAD4 genome AF: 0.000301 AC: 34 AN: 112792 Hom.: 0 Cov.: 24 AF XY: 0.000572 AC XY: 20 AN XY: 34990

African (AFR) AF: 0.000128 AC: 4 AN: 31187

American (AMR) AF: 0.0000922 AC: 1 AN: 10851

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3496

South Asian (SAS) AF: 0.00 AC: 0 AN: 2740

European-Finnish (FIN) AF: 0.00381 AC: 24 AN: 6293

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53125

Other (OTH) AF: 0.00 AC: 0 AN: 1546

Alfa AF: 0.000255 Hom.: 3

Bravo AF: 0.0000718

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Benign:2

May 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		-0.023
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs183801635; hg19: chrX-68836212;