X-110681487-C-T

Variant names:

• chrX-110681487-C-T
• rs144417315
• NM_001143981.2:c.1151G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001143981.2(CHRDL1):​c.1151G>A​(p.Arg384Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 1,205,073 control chromosomes in the GnomAD database, including 4 homozygotes. There are 237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., 124 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (2 hom. 113 hem.)
• Consequence: CHRDL1 NM_001143981.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.575
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006048888).
• BP6: Variant X-110681487-C-T is Benign according to our data. Variant chrX-110681487-C-T is described in ClinVar as Benign. ClinVar VariationId is 777821.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00382 (428/112062) while in subpopulation AFR AF = 0.0114 (353/30861). AF 95% confidence interval is 0.0105. There are 2 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143981.2. 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
	CHRDL1	NM_001143981.2	MANE Select	c.1151G>A	p.Arg384Gln	missense	Exon 10 of 12	NP_001137453.1	Q9BU40-4
	CHRDL1	NM_001367204.1		c.1151G>A	p.Arg384Gln	missense	Exon 10 of 12	NP_001354133.1	Q9BU40-4
	CHRDL1	NM_001143982.2		c.1148G>A	p.Arg383Gln	missense	Exon 10 of 12	NP_001137454.1	Q9BU40-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRDL1	ENST00000372042.6	TSL:2 MANE Select	c.1151G>A	p.Arg384Gln	missense	Exon 10 of 12	ENSP00000361112.1	Q9BU40-4
	CHRDL1	ENST00000444321.2	TSL:1	c.1148G>A	p.Arg383Gln	missense	Exon 10 of 12	ENSP00000399739.2	Q9BU40-5
	CHRDL1	ENST00000372045.5	TSL:1	c.1127G>A	p.Arg376Gln	missense	Exon 10 of 12	ENSP00000361115.1	A0A452Q6Z9

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 428 AN: 112009 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00535

GnomAD2 exomes AF: 0.00113 AC: 202 AN: 179021 AF XY: 0.000784

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000735

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000496

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000384 AC: 420 AN: 1093011 Hom.: 2 Cov.: 28 AF XY: 0.000315 AC XY: 113 AN XY: 358675

African (AFR) AF: 0.00966 AC: 254 AN: 26286

American (AMR) AF: 0.00190 AC: 66 AN: 34824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19245

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30169

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53219

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40488

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4114

European-Non Finnish (NFE) AF: 0.0000620 AC: 52 AN: 838757

Other (OTH) AF: 0.000958 AC: 44 AN: 45909

GnomAD4 genome AF: 0.00382 AC: 428 AN: 112062 Hom.: 2 Cov.: 23 AF XY: 0.00362 AC XY: 124 AN XY: 34234

African (AFR) AF: 0.0114 AC: 353 AN: 30861

American (AMR) AF: 0.00595 AC: 63 AN: 10586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2649

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6092

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53237

Other (OTH) AF: 0.00528 AC: 8 AN: 1514

Alfa AF: 0.00491 Hom.: 50

Bravo AF: 0.00477

ESP6500AA AF: 0.0107 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.57
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.026
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.33
MPC		0.39
ClinPred		0.021	T
GERP RS		2.2
Varity_R		0.056
gMVP		0.77
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144417315; hg19: chrX-109924715; COSMIC: COSV54326462;