dbSNP rs28941785: CTH:p.Thr67Ile (chr1-70415987-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 6P and 5B. PS3PP3PP5BP4BS2

The NM_001902.6(CTH):c.200C>T(p.Thr67Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00803 in 1,610,620 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000358891: Functional studies by Kraus et al. (2009) and Zhu et al. (2008) demonstrated that the p.Thr67Ile variant protein has decreased catalytic activity of 13 - 29% compared to wild type." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.0067 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 71 hom. )

Consequence

CTH
NM_001902.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 6.10

Publications

28 publications found

Variant links:

Genes affected

CTH (HGNC:2501): (cystathionine gamma-lyase) This gene encodes a cytoplasmic enzyme in the trans-sulfuration pathway that converts cystathione derived from methionine into cysteine. Glutathione synthesis in the liver is dependent upon the availability of cysteine. Mutations in this gene cause cystathioninuria. Alternative splicing of this gene results in three transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

CTH Gene-Disease associations (from GenCC):

cystathioninuria
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen

CTH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000358891: Functional studies by Kraus et al. (2009) and Zhu et al. (2008) demonstrated that the p.Thr67Ile variant protein has decreased catalytic activity of 13 - 29% compared to wild type.; SCV005360655: This variant has been shown to decrease the activity of the CTH protein substantially relative to the wild-type protein, and has previously been reported to be causative for cystathioninuria (Wang and Hegele. 2003. PubMed ID: 12574942; Zhu et al. 2008. PubMed ID: 18476726; Kraus et al. 2009. PubMed ID: 19428278; Espinós et al. 2010. PubMed ID: 20584029).

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 1-70415987-C-T is Pathogenic according to our data. Variant chr1-70415987-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2939.

BP4

Computational evidence support a benign effect (MetaRNN=0.023492247). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001902.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTH	NM_001902.6	MANE Select	c.200C>T	p.Thr67Ile	missense	Exon 2 of 12	NP_001893.2
CTH	NM_001190463.2		c.200C>T	p.Thr67Ile	missense	Exon 2 of 11	NP_001177392.1	P32929-3
CTH	NM_153742.5		c.200C>T	p.Thr67Ile	missense	Exon 2 of 11	NP_714964.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTH	ENST00000370938.8	TSL:1 MANE Select	c.200C>T	p.Thr67Ile	missense	Exon 2 of 12	ENSP00000359976.3	P32929-1
CTH	ENST00000346806.2	TSL:1	c.200C>T	p.Thr67Ile	missense	Exon 2 of 11	ENSP00000311554.2	P32929-2
CTH	ENST00000896200.1		c.200C>T	p.Thr67Ile	missense	Exon 3 of 13	ENSP00000566259.1

Frequencies

GnomAD3 genomes

AF:

0.00675

AC:

1027

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00939

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00648

AC:

1628

AN:

251408

AF XY:

0.00629

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00766

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00936

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00816

AC:

11900

AN:

1458344

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

5760

AN XY:

725702

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

33412

American (AMR)

AF:

0.00796

AC:

356

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00843

AC:

220

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00166

AC:

143

AN:

86180

European-Finnish (FIN)

AF:

0.00391

AC:

209

AN:

53410

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00943

AC:

10458

AN:

1108788

Other (OTH)

AF:

0.00720

AC:

434

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

538

1075

1613

2150

2688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00674

AC:

1027

AN:

152276

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41566

American (AMR)

AF:

0.0149

AC:

228

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00274

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00940

AC:

639

AN:

68014

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00815

Hom.:

Bravo

AF:

0.00708

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00647

AC:

786

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.00921

EpiControl

AF:

0.00996

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystathioninuria (5)

not provided (2)

CTH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.023

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.5

PhyloP100

6.1

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.87

MVP

0.99

MPC

0.66

ClinPred

0.063

GERP RS

5.5

Varity_R

0.94

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over