chr8-103371672-C-T

Variant names:

• chr8-103371672-C-T
• rs1437885778
• NM_138455.4:c.16C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS2_Supporting

The NM_138455.4(CTHRC1):​c.16C>T​(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,534,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: CTHRC1 NM_138455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• 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]

CTHRC1 Gene-Disease associations (from GenCC):

• Barrett esophagus

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• 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=0.084291786).
• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.16C>T	p.Pro6Ser	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.16C>T	p.Pro6Ser	missense	Exon 1 of 4	ENSP00000330523.5	Q96CG8-1
	CTHRC1	ENST00000891015.1		c.16C>T	p.Pro6Ser	missense	Exon 1 of 4	ENSP00000561074.1
	CTHRC1	ENST00000415886.2	TSL:2	c.16C>T	p.Pro6Ser	missense	Exon 1 of 2	ENSP00000416045.2	E7EVQ5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000579 AC: 8 AN: 1381740 Hom.: 0 Cov.: 31 AF XY: 0.00000881 AC XY: 6 AN XY: 681130

African (AFR) AF: 0.000138 AC: 4 AN: 29008

American (AMR) AF: 0.00 AC: 0 AN: 34632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24498

East Asian (EAS) AF: 0.0000293 AC: 1 AN: 34142

South Asian (SAS) AF: 0.00 AC: 0 AN: 77566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073358

Other (OTH) AF: 0.0000525 AC: 3 AN: 57116

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

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	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	0.24	T
Sift4G	Benign	0.53	T
Polyphen		0.0070	B
Vest4		0.12
MutPred		0.12		Gain of MoRF binding (P = 0.0211)
MVP		0.50
MPC		0.20
ClinPred		0.13	T
GERP RS		2.6
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.060
gMVP		0.21
Mutation Taster		=87/13	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: rs1437885778; hg19: chr8-104383900;