NM_138455.4:c.4C>G

Variant names:

• chr8-103371660-C-G
• rs202192964
• NM_138455.4:c.4C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_138455.4(CTHRC1):​c.4C>G​(p.Arg2Gly) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTHRC1 NM_138455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

Genes affected

CTHRC1 (HGNC:18831): (collagen triple helix repeat containing 1) This locus encodes a protein that may play a role in the cellular response to arterial injury through involvement in vascular remodeling. Mutations at this locus have been associated with Barrett esophagus and esophageal adenocarcinoma. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

BAALC-AS1 (HGNC:50461): (BAALC antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.63347 (below the threshold of 3.09). Trascript score misZ: 0.39942 (below the threshold of 3.09). GenCC associations: The gene is linked to Barrett esophagus.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21206886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138455.4. 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
	CTHRC1	NM_138455.4	MANE Select	c.4C>G	p.Arg2Gly	missense	Exon 1 of 4	NP_612464.1	Q96CG8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTHRC1	ENST00000330295.10	TSL:1 MANE Select	c.4C>G	p.Arg2Gly	missense	Exon 1 of 4	ENSP00000330523.5	Q96CG8-1
	CTHRC1	ENST00000891015.1		c.4C>G	p.Arg2Gly	missense	Exon 1 of 4	ENSP00000561074.1
	CTHRC1	ENST00000415886.2	TSL:2	c.4C>G	p.Arg2Gly	missense	Exon 1 of 2	ENSP00000416045.2	E7EVQ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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	0.083
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.18
Sift	Benign	0.055	T
Sift4G	Uncertain	0.033	D
Polyphen		0.0	B
Vest4		0.23
MutPred		0.20		Gain of catalytic residue at R2 (P = 0.0327)
MVP		0.79
MPC		0.25
ClinPred		0.55	D
GERP RS		2.9
PromoterAI		0.047	Neutral
Varity_R		0.085
gMVP		0.41
Mutation Taster		=90/10	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: rs202192964; hg19: chr8-104383888;