rs387907029

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP2PP5BP4BS2_Supporting

The NM_138455.4(CTHRC1):c.131A>C(p.Gln44Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,533,038 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q44H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CTHRC1
NM_138455.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.535

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 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.

PP5

Variant 8-103371787-A-C is Pathogenic according to our data. Variant chr8-103371787-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 30848.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-103371787-A-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.093295276). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 15 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 link	c.131A>C	p.Gln44Pro	missense_variant	Exon 1 of 4	ENST00000330295.10	NP_612464.1	Q96CG8-1
CTHRC1	XM_011516824.3 link	c.131A>C	p.Gln44Pro	missense_variant	Exon 1 of 3		XP_011515126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTHRC1	ENST00000330295.10 link	c.131A>C	p.Gln44Pro	missense_variant	Exon 1 of 4	1	NM_138455.4	ENSP00000330523.5		Q96CG8-1
CTHRC1	ENST00000415886.2 link	c.131A>C	p.Gln44Pro	missense_variant	Exon 1 of 2	2		ENSP00000416045.2		E7EVQ5

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000231

AC:

AN:

129726

AF XY:

0.0000143

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000657

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

139

AN:

1380852

Hom.:

Cov.:

AF XY:

0.0000750

AC XY:

AN XY:

680368

show subpopulations

African (AFR)

AF:

0.0000342

AC:

AN:

29246

American (AMR)

AF:

0.00

AC:

AN:

34364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24450

East Asian (EAS)

AF:

0.00

AC:

AN:

34214

South Asian (SAS)

AF:

0.00

AC:

AN:

77276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4614

European-Non Finnish (NFE)

AF:

0.000127

AC:

136

AN:

1071502

Other (OTH)

AF:

0.0000350

AC:

AN:

57184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000133

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMA

Pathogenic:1

Jul 27, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.093

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

N;.

PhyloP100

0.54

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.62

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.15

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;B

Vest4

0.17

MVP

0.68

MPC

0.23

ClinPred

0.049

GERP RS

2.4

PromoterAI

0.089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.44

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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rs387907029

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over