8-103375958-C-A

Variant names:

• chr8-103375958-C-A
• rs374084026
• NM_138455.4:c.371C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138455.4(CTHRC1):​c.371C>A​(p.Ala124Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,456,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTHRC1 NM_138455.4 missense, splice_region
• Scores: Splicing: ADA: 0.09588
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTHRC1	NM_138455.4	c.371C>A	p.Ala124Glu	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000330295.10	NP_612464.1
CTHRC1	NM_001256099.2	c.329C>A	p.Ala110Glu	missense_variant, splice_region_variant	Exon 2 of 4		NP_001243028.1
CTHRC1	XM_011516824.3	c.371C>A	p.Ala124Glu	missense_variant, splice_region_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.371C>A	p.Ala124Glu	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_138455.4	ENSP00000330523.5
CTHRC1	ENST00000520337.1	c.329C>A	p.Ala110Glu	missense_variant, splice_region_variant	Exon 2 of 4	1		ENSP00000430550.1
CTHRC1	ENST00000415886.2	c.371C>A	p.Ala124Glu	missense_variant	Exon 2 of 2	2		ENSP00000416045.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247724 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456266 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724458

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;T;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.14	T;D;T
Sift4G	Benign	0.42	T;D;T
Polyphen		0.80	P;D;.
Vest4		0.71
MutPred		0.27		Gain of ubiquitination at K122 (P = 0.0798);Gain of ubiquitination at K122 (P = 0.0798);.;
MVP		0.88
MPC		0.43
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.096
dbscSNV1_RF	Benign	0.33
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: rs374084026; hg19: chr8-104388186;