rs145871696

chr3-184383572-C-Gchr3-184383572-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_003741.4(CHRD):c.1370C>G(p.Thr457Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CHRD NM_003741.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1651772).
• BP6: Variant 3-184383572-C-G is Benign according to our data. Variant chr3-184383572-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 221946.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRD	NM_003741.4	c.1370C>G	p.Thr457Ser	missense_variant	12/23	ENST00000204604.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRD	ENST00000204604.6	c.1370C>G	p.Thr457Ser	missense_variant	12/23	1	NM_003741.4	P4

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.000309

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000330 AC: 83 AN: 251138 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135754

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.000213 AC XY: 155 AN XY: 727216

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74340

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.000756

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anophthalmia-microphthalmia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.59	D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.091
Sift	Benign	0.056	T;T
Sift4G	Uncertain	0.043	D;D
Polyphen		1.0	D;B
Vest4		0.50
MutPred		0.42		Gain of disorder (P = 0.0556);Gain of disorder (P = 0.0556);
MVP		0.74
MPC		0.99
ClinPred		0.035	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs145871696; hg19: chr3-184101360; COSMIC: COSV52606570; COSMIC: COSV52606570;