8-103378121-G-A

Position:

chr8-103378121-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The NM_138455.4(CTHRC1):c.467G>A(p.Arg156His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,614,162 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

CTHRC1
NM_138455.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.60

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.097035766).

BS2

High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CTHRC1	NM_138455.4 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	3/4	ENST00000330295.10	NP_612464.1
CTHRC1	NM_001256099.2 linkuse as main transcript	c.425G>A	p.Arg142His	missense_variant	3/4		NP_001243028.1
CTHRC1	XM_011516824.3 linkuse as main transcript	c.372+2162G>A		intron_variant			XP_011515126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTHRC1	ENST00000330295.10 linkuse as main transcript	c.467G>A	p.Arg156His	missense_variant	3/4	1	NM_138455.4	ENSP00000330523	P1	Q96CG8-1
CTHRC1	ENST00000520337.1 linkuse as main transcript	c.425G>A	p.Arg142His	missense_variant	3/4	1		ENSP00000430550		Q96CG8-3
CTHRC1	ENST00000520880.1 linkuse as main transcript	c.77G>A	p.Arg26His	missense_variant	2/3	4		ENSP00000430399

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000334

AC:

AN:

251242

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152330

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CTHRC1 p.Arg142His variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145062750) and was found in control databases in 113 of 282640 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 87 of 24968 chromosomes (freq: 0.003484), South Asian in 18 of 30612 chromosomes (freq: 0.000588), Other in 1 of 7218 chromosomes (freq: 0.000139), Latino in 2 of 35436 chromosomes (freq: 0.000056), East Asian in 1 of 19952 chromosomes (freq: 0.00005) and European (non-Finnish) in 4 of 128968 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg142 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.097

T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.8

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MVP

0.88

MPC

0.85

ClinPred

0.15

GERP RS

5.5

Varity_R

0.81

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over