chr8-103375913-G-T

Variant names:

• chr8-103375913-G-T
• rs775361593
• NM_138455.4:c.326G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138455.4(CTHRC1):​c.326G>T​(p.Cys109Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTHRC1	NM_138455.4	c.326G>T	p.Cys109Phe	missense_variant	Exon 2 of 4	ENST00000330295.10	NP_612464.1
CTHRC1	NM_001256099.2	c.284G>T	p.Cys95Phe	missense_variant	Exon 2 of 4		NP_001243028.1
CTHRC1	XM_011516824.3	c.326G>T	p.Cys109Phe	missense_variant	Exon 2 of 3		XP_011515126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTHRC1	ENST00000330295.10	c.326G>T	p.Cys109Phe	missense_variant	Exon 2 of 4	1	NM_138455.4	ENSP00000330523.5
CTHRC1	ENST00000520337.1	c.284G>T	p.Cys95Phe	missense_variant	Exon 2 of 4	1		ENSP00000430550.1
CTHRC1	ENST00000415886.2	c.326G>T	p.Cys109Phe	missense_variant	Exon 2 of 2	2		ENSP00000416045.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326G>T (p.C109F) alteration is located in exon 2 (coding exon 2) of the CTHRC1 gene. This alteration results from a G to T substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.84		Gain of ubiquitination at K107 (P = 0.1245);Gain of ubiquitination at K107 (P = 0.1245);.;
MVP		0.91
MPC		0.92
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.94

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: rs775361593; hg19: chr8-104388141;