3-184383572-C-T

Variant names:

• chr3-184383572-C-T
• rs145871696
• NM_003741.4:c.1370C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003741.4(CHRD):​c.1370C>T​(p.Thr457Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T457S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRD NM_003741.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69
• Publications: 3 publications found

Genes affected

CHRD (HGNC:1949): (chordin) This gene encodes a secreted protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta-like bone morphogenetic proteins and sequestering them in latent complexes. The encoded protein may also have roles in organogenesis and during adulthood. It has been suggested that this gene could be a candidate gene for Cornelia de Lange syndrome. Reduced expression of this gene results in enhanced bone regeneration. Alternative splicing results in multiple transcript variants. Other alternative splice variants have been described but their full length sequence has not been determined. [provided by RefSeq, Jan 2015]

CHRD Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
CHRD	NM_003741.4	c.1370C>T	p.Thr457Ile	missense_variant	Exon 12 of 23	ENST00000204604.6	NP_003732.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRD	ENST00000204604.6	c.1370C>T	p.Thr457Ile	missense_variant	Exon 12 of 23	1	NM_003741.4	ENSP00000204604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.99	D;B
Vest4		0.76
MutPred		0.54		Gain of catalytic residue at P459 (P = 0.0307);Gain of catalytic residue at P459 (P = 0.0307);
MVP		0.74
MPC		1.1
ClinPred		0.91	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.64
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs145871696; hg19: chr3-184101360;