X-110694315-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001143981.2(CHRDL1):c.626G>A(p.Arg209His) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,202,666 control chromosomes in the GnomAD database, including 21 homozygotes. There are 720 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (10 hom., 297 hem., cov: 22)
  • Exomes 𝑓: 0.0013 (11 hom. 423 hem.)
• Consequence: CHRDL1 NM_001143981.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.91

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009160072).
• BP6: Variant X-110694315-C-T is Benign according to our data. Variant chrX-110694315-C-T is described in ClinVar as [Benign]. Clinvar id is 788059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00916 (1023/111669) while in subpopulation AFR AF= 0.0291 (893/30727). AF 95% confidence interval is 0.0275. There are 10 homozygotes in gnomad4. There are 297 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRDL1	NM_001143981.2	c.626G>A	p.Arg209His	missense_variant	8/12	ENST00000372042.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRDL1	ENST00000372042.6	c.626G>A	p.Arg209His	missense_variant	8/12	2	NM_001143981.2	A1

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1020 AN: 111619 Hom.: 10 Cov.: 22 AF XY: 0.00869 AC XY: 294 AN XY: 33833

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00503

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000377

Gnomad OTH AF: 0.0133

GnomAD3 exomes AF: 0.00379 AC: 673 AN: 177767 Hom.: 6 AF XY: 0.00271 AC XY: 170 AN XY: 62633

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.000140

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00134 AC: 1465 AN: 1090997 Hom.: 11 Cov.: 29 AF XY: 0.00119 AC XY: 423 AN XY: 356739

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.000105

Gnomad4 EAS exome AF: 0.00863

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00916 AC: 1023 AN: 111669 Hom.: 10 Cov.: 22 AF XY: 0.00876 AC XY: 297 AN XY: 33893

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.00502

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000377

Gnomad4 OTH AF: 0.0131

Alfa AF: 0.00369 Hom.: 37

Bravo AF: 0.0103

ESP6500AA AF: 0.0313 AC: 120

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00389 AC: 472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2018

- -

CHRDL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;.;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;.;.;.;.
MutationTaster	Benign	0.0000076	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.50	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.042	D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.25
MVP		0.42
MPC		1.2
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs12688415; hg19: chrX-109937543;