X-66602765-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021783.5(EDA2R):​c.385A>G​(p.Thr129Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 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: 𝑓 0.94 (34351 hom., 29940 hem., cov: 22)
  • Exomes 𝑓: 0.99 (360513 hom. 352687 hem.)
  • Failed GnomAD Quality Control
• Consequence: EDA2R NM_021783.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 24 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1831476E-6).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA2R	NM_021783.5	c.385A>G	p.Thr129Ala	missense_variant	Exon 5 of 7	ENST00000374719.8	NP_068555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA2R	ENST00000374719.8	c.385A>G	p.Thr129Ala	missense_variant	Exon 5 of 7	1	NM_021783.5	ENSP00000363851.3
EDA2R	ENST00000253392.5	c.385A>G	p.Thr129Ala	missense_variant	Exon 4 of 6	1		ENSP00000253392.5
EDA2R	ENST00000396050.5	c.385A>G	p.Thr129Ala	missense_variant	Exon 4 of 7	5		ENSP00000379365.2
EDA2R	ENST00000451436.6	c.385A>G	p.Thr129Ala	missense_variant	Exon 5 of 7	5		ENSP00000415242.3

Frequencies

GnomAD3 genomes AF: 0.936 AC: 102510 AN: 109538 Hom.: 34354 Cov.: 22

Gnomad AFR AF: 0.776

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.996

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.955

GnomAD2 exomes AF: 0.981 AC: 149078 AN: 151976 AF XY: 0.989

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.992

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.993 AC: 1078064 AN: 1085336 Hom.: 360513 Cov.: 39 AF XY: 0.995 AC XY: 352687 AN XY: 354566

African (AFR) AF: 0.774 AC: 20233 AN: 26140

American (AMR) AF: 0.988 AC: 33180 AN: 33585

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 18998 AN: 19009

East Asian (EAS) AF: 1.00 AC: 29617 AN: 29617

South Asian (SAS) AF: 1.00 AC: 51997 AN: 52023

European-Finnish (FIN) AF: 1.00 AC: 39767 AN: 39767

Middle Eastern (MID) AF: 0.993 AC: 4021 AN: 4048

European-Non Finnish (NFE) AF: 1.00 AC: 835371 AN: 835562

Other (OTH) AF: 0.985 AC: 44880 AN: 45585

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.936 AC: 102558 AN: 109596 Hom.: 34351 Cov.: 22 AF XY: 0.940 AC XY: 29940 AN XY: 31844

African (AFR) AF: 0.776 AC: 23268 AN: 29989

American (AMR) AF: 0.979 AC: 10043 AN: 10263

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 2617 AN: 2619

East Asian (EAS) AF: 1.00 AC: 3431 AN: 3431

South Asian (SAS) AF: 0.999 AC: 2488 AN: 2491

European-Finnish (FIN) AF: 1.00 AC: 5733 AN: 5733

Middle Eastern (MID) AF: 0.995 AC: 216 AN: 217

European-Non Finnish (NFE) AF: 1.00 AC: 52671 AN: 52696

Other (OTH) AF: 0.955 AC: 1417 AN: 1483

Alfa AF: 0.990 Hom.: 77622

Bravo AF: 0.926

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 1.00 AC: 2888

ESP6500AA AF: 0.778 AC: 2985

ESP6500EA AF: 1.00 AC: 6723

ExAC AF: 0.978 AC: 115776

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.7
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T;.;T;.
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.039	.;T;T;.
MetaRNN	Benign	0.0000012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;N;N
PhyloP100		0.042
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.070	N;N;.;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.016
ClinPred		0.0063	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.26
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV53630236;