rs1057516043

Variant names:

• chrX-110719855-G-GA
• rs1057516043
• NM_001143981.2:c.520dupT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001143981.2(CHRDL1):​c.520dupT​(p.Ser174PhefsTer18) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: CHRDL1 NM_001143981.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11
• Publications: 1 publications found

Genes affected

CHRDL1 (HGNC:29861): (chordin like 1) This gene encodes an antagonist of bone morphogenetic protein 4. The encoded protein may play a role in topographic retinotectal projection and in the regulation of retinal angiogenesis in response to hypoxia. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jan 2009]

CHRDL1 Gene-Disease associations (from GenCC):

• isolated congenital megalocornea

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-110719855-G-GA is Pathogenic according to our data. Variant chrX-110719855-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 369678.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRDL1	NM_001143981.2	c.520dupT	p.Ser174PhefsTer18	frameshift_variant	Exon 6 of 12	ENST00000372042.6	NP_001137453.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRDL1	ENST00000372042.6	c.520dupT	p.Ser174PhefsTer18	frameshift_variant	Exon 6 of 12	2	NM_001143981.2	ENSP00000361112.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Megalocornea Pathogenic:1

Nov 03, 2014

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication results ina frameshift and premature truncation 18 amino acids downstream, prior to the final highly conserved cysteine-rich VWFC domain. This variant is prediceted to be disease-causing by in-silico software. This is a novel truncating variant not present in disease or population databases. It was identified in a male with clinical features of the condition. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1057516043; hg19: chrX-109963083;