3-184381505-G-T

Variant names:

• chr3-184381505-G-T
• NM_003741.4:c.392G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003741.4(CHRD):​c.392G>T​(p.Ser131Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRD NM_003741.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103
• Publications: 0 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]

THPO (HGNC:11795): (thrombopoietin) Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5' UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent. [provided by RefSeq, Feb 2014]

THPO Gene-Disease associations (from GenCC):

• thrombocythemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• congenital amegakaryocytic thrombocytopenia

  Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• thrombocytopenia 9

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytosis with transverse limb defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050538063).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRD	NM_003741.4	MANE Select	c.392G>T	p.Ser131Ile	missense	Exon 4 of 23	NP_003732.2
	CHRD	NM_001304472.2		c.392G>T	p.Ser131Ile	missense	Exon 4 of 23	NP_001291401.1	E7ESX1
	CHRD	NM_001304473.2		c.-690G>T		5_prime_UTR	Exon 5 of 24	NP_001291402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRD	ENST00000204604.6	TSL:1 MANE Select	c.392G>T	p.Ser131Ile	missense	Exon 4 of 23	ENSP00000204604.1	Q9H2X0-1
	CHRD	ENST00000450923.5	TSL:1	c.392G>T	p.Ser131Ile	missense	Exon 4 of 23	ENSP00000408972.1	E7ESX1
	CHRD	ENST00000356534.7	TSL:1	n.*182G>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000348930.3	Q9H2X0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.10
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.0060
Sift	Benign	0.18	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0050	B
Vest4		0.20
MutPred		0.20		Gain of glycosylation at S131 (P = 0.0055)
MVP		0.26
MPC		0.39
ClinPred		0.080	T
GERP RS		-0.80
PromoterAI		-0.0026	Neutral
Varity_R		0.075
gMVP		0.49
Mutation Taster		=97/3	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

hg19: chr3-184099293;