rs1385698

Variant names:

• chrX-66602765-T-A
• rs1385698
• NM_021783.5:c.385A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-66602765-T-A
• chrX-66602765-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021783.5(EDA2R):​c.385A>T​(p.Thr129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,085,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 0 publications found

Genes affected

EDA2R (HGNC:17756): (ectodysplasin A2 receptor) The protein encoded by this gene is a type III transmembrane protein of the TNFR (tumor necrosis factor receptor) superfamily, and contains cysteine-rich repeats and a single transmembrane domain. This protein binds to the EDA-A2 isoform of ectodysplasin, which plays an important role in maintenance of hair and teeth. Alternatively spliced transcript variants encodes distinct protein isoforms. [provided by RefSeq, Apr 2016]

EDA2R Gene-Disease associations (from GenCC):

• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04124978).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	NM_021783.5	MANE Select	c.385A>T	p.Thr129Ser	missense	Exon 5 of 7	NP_068555.2	Q9HAV5-1
	EDA2R	NM_001242310.1		c.385A>T	p.Thr129Ser	missense	Exon 4 of 7	NP_001229239.1	Q9HAV5
	EDA2R	NM_001324206.2		c.385A>T	p.Thr129Ser	missense	Exon 5 of 7	NP_001311135.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA2R	ENST00000374719.8	TSL:1 MANE Select	c.385A>T	p.Thr129Ser	missense	Exon 5 of 7	ENSP00000363851.3	Q9HAV5-1
	EDA2R	ENST00000253392.5	TSL:1	c.385A>T	p.Thr129Ser	missense	Exon 4 of 6	ENSP00000253392.5	Q9HAV5-2
	EDA2R	ENST00000396050.5	TSL:5	c.385A>T	p.Thr129Ser	missense	Exon 4 of 7	ENSP00000379365.2	Q9HAV5-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1085354 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 354574

⚠️ 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: 26147

American (AMR) AF: 0.00 AC: 0 AN: 33589

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19009

East Asian (EAS) AF: 0.00 AC: 0 AN: 29617

South Asian (SAS) AF: 0.00 AC: 0 AN: 52024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39767

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835567

Other (OTH) AF: 0.00 AC: 0 AN: 45586

⚠️ 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 Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.0
DANN	Benign	0.14
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.042
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.15
Sift	Benign	0.77	T
Sift4G	Benign	0.98	T
Polyphen		0.0010	B
Vest4		0.049
MutPred		0.25		Gain of disorder (P = 0.0619)
MVP		0.79
ClinPred		0.023	T
GERP RS		3.5
Varity_R		0.053
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1385698; hg19: chrX-65822607;