Genetic Variant CHRDL1:p.Phe421Leu (chrX-110676347-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001143981.2(CHRDL1):c.1261T>C(p.Phe421Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,097,020 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CHRDL1
NM_001143981.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.43

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39211416).

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.1261T>C	p.Phe421Leu	missense	Exon 12 of 12	NP_001137453.1	Q9BU40-4
CHRDL1	NM_001367204.1		c.1261T>C	p.Phe421Leu	missense	Exon 12 of 12	NP_001354133.1	Q9BU40-4
CHRDL1	NM_001143982.2		c.1258T>C	p.Phe420Leu	missense	Exon 12 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.1261T>C	p.Phe421Leu	missense	Exon 12 of 12	ENSP00000361112.1	Q9BU40-4
CHRDL1	ENST00000444321.2	TSL:1	c.1258T>C	p.Phe420Leu	missense	Exon 12 of 12	ENSP00000399739.2	Q9BU40-5
CHRDL1	ENST00000372045.5	TSL:1	c.1237T>C	p.Phe413Leu	missense	Exon 12 of 12	ENSP00000361115.1	A0A452Q6Z9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

182113

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1097020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26347

American (AMR)

AF:

0.00

AC:

AN:

35104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19344

East Asian (EAS)

AF:

0.00

AC:

AN:

30185

South Asian (SAS)

AF:

0.00

AC:

AN:

54065

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40453

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841358

Other (OTH)

AF:

0.00

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.049

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.63

PhyloP100

6.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.4

REVEL

Benign

0.059

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.57

MutPred

0.38

Gain of sheet (P = 0.0344)

MVP

0.45

MPC

0.40

ClinPred

0.81

GERP RS

4.8

Varity_R

0.63

gMVP

0.95

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over