rs142948132

Variant names:

• chrX-70035434-G-A
• rs142948132
• NM_001399.5:c.1001G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-70035434-G-A
• chrX-70035434-G-C
• chrX-70035434-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001399.5(EDA):​c.1001G>A​(p.Arg334His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,207,703 control chromosomes in the GnomAD database, including 4 homozygotes. There are 137 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00065 (1 hom., 22 hem., cov: 21)
  • Exomes 𝑓: 0.00035 (3 hom. 115 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 9.25
• Publications: 15 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, Labcorp Genetics (formerly Invitae), Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001399.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010842383).
• BP6: Variant X-70035434-G-A is Benign according to our data. Variant chrX-70035434-G-A is described in ClinVar as Benign. ClinVar VariationId is 253055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000654 (72/110131) while in subpopulation EAS AF = 0.0146 (51/3501). AF 95% confidence interval is 0.0114. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. 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
	EDA	NM_001399.5	MANE Select	c.1001G>A	p.Arg334His	missense	Exon 8 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.995G>A	p.Arg332His	missense	Exon 8 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.992G>A	p.Arg331His	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.1001G>A	p.Arg334His	missense	Exon 8 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.995G>A	p.Arg332His	missense	Exon 8 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.986G>A	p.Arg329His	missense	Exon 8 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 73 AN: 110077 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000970

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.000396

Gnomad FIN AF: 0.000345

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.000678

GnomAD2 exomes AF: 0.000920 AC: 166 AN: 180407 AF XY: 0.000705

Gnomad AFR exome AF: 0.000539

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00999

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.0000500

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.000354 AC: 389 AN: 1097572 Hom.: 3 Cov.: 31 AF XY: 0.000317 AC XY: 115 AN XY: 362942

African (AFR) AF: 0.000152 AC: 4 AN: 26384

American (AMR) AF: 0.0000284 AC: 1 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00504 AC: 152 AN: 30177

South Asian (SAS) AF: 0.000444 AC: 24 AN: 54020

European-Finnish (FIN) AF: 0.000247 AC: 10 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000170 AC: 143 AN: 841764

Other (OTH) AF: 0.00119 AC: 55 AN: 46078

GnomAD4 genome AF: 0.000654 AC: 72 AN: 110131 Hom.: 1 Cov.: 21 AF XY: 0.000679 AC XY: 22 AN XY: 32395

African (AFR) AF: 0.000265 AC: 8 AN: 30220

American (AMR) AF: 0.0000969 AC: 1 AN: 10322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2629

East Asian (EAS) AF: 0.0146 AC: 51 AN: 3501

South Asian (SAS) AF: 0.000397 AC: 1 AN: 2520

European-Finnish (FIN) AF: 0.000345 AC: 2 AN: 5805

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000152 AC: 8 AN: 52741

Other (OTH) AF: 0.000669 AC: 1 AN: 1495

Alfa AF: 0.000292 Hom.: 8

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000692 AC: 84

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hypohidrotic X-linked ectodermal dysplasia (2)
1	-	1	Tooth agenesis, selective, X-linked, 1 (2)
-	-	1	Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)
-	-	1	not specified (1)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.2	L
PhyloP100		9.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.26
MVP		1.0
MPC		1.5
ClinPred		0.058	T
GERP RS		5.5
Varity_R		0.89
gMVP		0.86
Mutation Taster		=71/29	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs142948132; hg19: chrX-69255284;