chr3-184383572-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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003741.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRD	NM_003741.4	MANE Select	c.1370C>T	p.Thr457Ile	missense	Exon 12 of 23	NP_003732.2
	CHRD	NM_001304472.2		c.1370C>T	p.Thr457Ile	missense	Exon 12 of 23	NP_001291401.1
	CHRD	NM_001304473.2		c.260C>T	p.Thr87Ile	missense	Exon 13 of 24	NP_001291402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRD	ENST00000204604.6	TSL:1 MANE Select	c.1370C>T	p.Thr457Ile	missense	Exon 12 of 23	ENSP00000204604.1
	CHRD	ENST00000450923.5	TSL:1	c.1370C>T	p.Thr457Ile	missense	Exon 12 of 23	ENSP00000408972.1
	CHRD	ENST00000420973.5	TSL:1	n.*288C>T		non_coding_transcript_exon	Exon 12 of 23	ENSP00000392794.1

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 v4.9

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
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.40	T
Sift4G	Benign	0.45	T
Polyphen		0.99	D
Vest4		0.76
MutPred		0.54		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;