X-110676338-C-T

Variant names:

• chrX-110676338-C-T
• rs771328892
• NM_001143981.2:c.1270G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001143981.2(CHRDL1):​c.1270G>A​(p.Gly424Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000827 in 1,208,964 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: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 0 hem.)
• Consequence: CHRDL1 NM_001143981.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31175).

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.1270G>A	p.Gly424Arg	missense	Exon 12 of 12	NP_001137453.1	Q9BU40-4
	CHRDL1	NM_001367204.1		c.1270G>A	p.Gly424Arg	missense	Exon 12 of 12	NP_001354133.1	Q9BU40-4
	CHRDL1	NM_001143982.2		c.1267G>A	p.Gly423Arg	missense	Exon 12 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.1270G>A	p.Gly424Arg	missense	Exon 12 of 12	ENSP00000361112.1	Q9BU40-4
	CHRDL1	ENST00000444321.2	TSL:1	c.1267G>A	p.Gly423Arg	missense	Exon 12 of 12	ENSP00000399739.2	Q9BU40-5
	CHRDL1	ENST00000372045.5	TSL:1	c.1246G>A	p.Gly416Arg	missense	Exon 12 of 12	ENSP00000361115.1	A0A452Q6Z9

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111902 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 8 AN: 182282 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000220

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: 0.000445

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097062 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 362696

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.000199 AC: 7 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19345

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54083

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841333

Other (OTH) AF: 0.00 AC: 0 AN: 46039

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111902 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30768

American (AMR) AF: 0.000190 AC: 2 AN: 10509

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6093

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1510

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.47	N
REVEL	Benign	0.20
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.050	T
Polyphen		0.94	P
Vest4		0.55
MutPred		0.51		Gain of solvent accessibility (P = 0.0171)
MVP		0.45
MPC		1.2
ClinPred		0.19	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.86
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs771328892; hg19: chrX-109919566;