8-103375837-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138455.4(CTHRC1):c.250G>A(p.Asp84Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTHRC1	NM_138455.4	c.250G>A	p.Asp84Asn	missense_variant	2/4	ENST00000330295.10
CTHRC1	NM_001256099.2	c.208G>A	p.Asp70Asn	missense_variant	2/4
CTHRC1	XM_011516824.3	c.250G>A	p.Asp84Asn	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTHRC1	ENST00000330295.10	c.250G>A	p.Asp84Asn	missense_variant	2/4	1	NM_138455.4	P1
CTHRC1	ENST00000520337.1	c.208G>A	p.Asp70Asn	missense_variant	2/4	1
CTHRC1	ENST00000415886.2	c.250G>A	p.Asp84Asn	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000274 AC: 4 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.250G>A (p.D84N) alteration is located in exon 2 (coding exon 2) of the CTHRC1 gene. This alteration results from a G to A substitution at nucleotide position 250, causing the aspartic acid (D) at amino acid position 84 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	0.51
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Uncertain	0.56
Sift	Benign	0.065	T;D;T
Sift4G	Uncertain	0.043	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.49		Gain of methylation at R83 (P = 0.1051);Gain of methylation at R83 (P = 0.1051);.;
MVP		0.96
MPC		0.70
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.50

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: rs1287051433; hg19: chr8-104388065;