NM_001143981.2:c.1273G>A

Variant names:

• chrX-110676335-C-T
• rs1237859978
• NM_001143981.2:c.1273G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001143981.2(CHRDL1):​c.1273G>A​(p.Glu425Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CHRDL1 NM_001143981.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRDL1	NM_001143981.2	c.1273G>A	p.Glu425Lys	missense_variant	Exon 12 of 12	ENST00000372042.6	NP_001137453.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRDL1	ENST00000372042.6	c.1273G>A	p.Glu425Lys	missense_variant	Exon 12 of 12	2	NM_001143981.2	ENSP00000361112.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182373 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67041

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1273G>A (p.E425K) alteration is located in exon 12 (coding exon 11) of the CHRDL1 gene. This alteration results from a G to A substitution at nucleotide position 1273, causing the glutamic acid (E) at amino acid position 425 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.78	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.042	D;D;D;D;D
Sift4G	Benign	0.063	T;T;T;T;T
Polyphen		0.18	B;.;.;.;.
Vest4		0.63
MutPred		0.47		Gain of MoRF binding (P = 0.0074);.;.;.;.;
MVP		0.49
MPC		0.50
ClinPred		0.37	T
GERP RS		4.8
Varity_R		0.42
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1237859978; hg19: chrX-109919563;