X-70027888-CCCTCCAGGACCCCCAGGA-CCCTCCAGGACCCCCAGGACCTCCAGGACCCCCAGGA

Variant names:

• chrX-70027888-C-CCCTCCAGGACCCCCAGGA
• rs397516668
• NM_001399.5:c.572_589dupCAGGACCTCCAGGACCCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM4 BS2

The NM_001399.5(EDA):​c.572_589dupCAGGACCTCCAGGACCCC​(p.Pro191_Pro196dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 914,619 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000066 (0 hom. 2 hem.)
• Consequence: EDA NM_001399.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.37
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001399.5
• PM4: Nonframeshift variant in NON repetitive region in NM_001399.5.
• BS2: High AC in GnomAdExome4 at 6 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.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 of 8	NP_001390.1
	EDA	NM_001005609.2		c.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 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.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.572_589dupCAGGACCTCCAGGACCCC	p.Pro191_Pro196dup	disruptive_inframe_insertion	Exon 4 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000788 AC: 1 AN: 126835 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000656 AC: 6 AN: 914619 Hom.: 0 Cov.: 18 AF XY: 0.00000782 AC XY: 2 AN XY: 255633

African (AFR) AF: 0.0000899 AC: 2 AN: 22242

American (AMR) AF: 0.00 AC: 0 AN: 29582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17911

East Asian (EAS) AF: 0.00 AC: 0 AN: 27338

South Asian (SAS) AF: 0.0000211 AC: 1 AN: 47317

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38257

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00000436 AC: 3 AN: 688293

Other (OTH) AF: 0.00 AC: 0 AN: 39933

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Hypohidrotic X-linked ectodermal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4

Splicing

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

Other links and lift over

dbSNP: rs397516668; hg19: chrX-69247738;