Genetic Variant CHRDL1:p.Lys314Thr (chrX-110688641-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001143981.2(CHRDL1):c.941A>C(p.Lys314Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K314R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CHRDL1
NM_001143981.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.66

Publications

0 publications found

Variant links:

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)

CHRDL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRDL1	NM_001143981.2	MANE Select	c.941A>C	p.Lys314Thr	missense	Exon 9 of 12	NP_001137453.1	Q9BU40-4
CHRDL1	NM_001367204.1		c.941A>C	p.Lys314Thr	missense	Exon 9 of 12	NP_001354133.1	Q9BU40-4
CHRDL1	NM_001143982.2		c.938A>C	p.Lys313Thr	missense	Exon 9 of 12	NP_001137454.1	Q9BU40-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRDL1	ENST00000372042.6	TSL:2 MANE Select	c.941A>C	p.Lys314Thr	missense	Exon 9 of 12	ENSP00000361112.1	Q9BU40-4
CHRDL1	ENST00000444321.2	TSL:1	c.938A>C	p.Lys313Thr	missense	Exon 9 of 12	ENSP00000399739.2	Q9BU40-5
CHRDL1	ENST00000372045.5	TSL:1	c.920A>C	p.Lys307Thr	missense	Exon 9 of 12	ENSP00000361115.1	A0A452Q6Z9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097916

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54135

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841849

Other (OTH)

AF:

0.00

AC:

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.77

PhyloP100

7.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.58

Sift

Benign

0.051

Sift4G

Benign

0.065

Polyphen

1.0

Vest4

0.73

MutPred

0.55

Loss of methylation at K307 (P = 0.0128)

MVP

0.91

MPC

1.2

ClinPred

0.96

GERP RS

5.0

Varity_R

0.60

gMVP

0.74

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over