8-103378079-G-A

Variant names:

• chr8-103378079-G-A
• NM_138455.4:c.425G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_138455.4(CTHRC1):​c.425G>A​(p.Ser142Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CTHRC1 NM_138455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68

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_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTHRC1	NM_138455.4	c.425G>A	p.Ser142Asn	missense_variant	Exon 3 of 4	ENST00000330295.10	NP_612464.1
CTHRC1	NM_001256099.2	c.383G>A	p.Ser128Asn	missense_variant	Exon 3 of 4		NP_001243028.1
CTHRC1	XM_011516824.3	c.372+2120G>A		intron_variant	Intron 2 of 2		XP_011515126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTHRC1	ENST00000330295.10	c.425G>A	p.Ser142Asn	missense_variant	Exon 3 of 4	1	NM_138455.4	ENSP00000330523.5
CTHRC1	ENST00000520337.1	c.383G>A	p.Ser128Asn	missense_variant	Exon 3 of 4	1		ENSP00000430550.1
CTHRC1	ENST00000520880.1	c.35G>A	p.Ser12Asn	missense_variant	Exon 2 of 3	4		ENSP00000430399.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.425G>A (p.S142N) alteration is located in exon 3 (coding exon 3) of the CTHRC1 gene. This alteration results from a G to A substitution at nucleotide position 425, causing the serine (S) at amino acid position 142 to be replaced by an asparagine (N). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.20	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.30	B;.;.
Vest4		0.74
MutPred		0.27		Loss of catalytic residue at S142 (P = 0.0336);.;.;
MVP		0.69
MPC		0.18
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-104390307;