1-70439117-G-T

Position:

chr1-70439117-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001902.6(CTH):c.1208G>T(p.Ser403Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,608,522 control chromosomes in the GnomAD database, including 66,116 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4981 hom., cov: 31)

Exomes 𝑓: 0.28 ( 61135 hom. )

Consequence

CTH
NM_001902.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.0840

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 links:

CTH (HGNC:):

CTH links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.174313E-4).

BP6

Variant 1-70439117-G-T is Benign according to our data. Variant chr1-70439117-G-T is described in ClinVar as [Benign]. Clinvar id is 2941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTH	NM_001902.6 linkuse as main transcript	c.1208G>T	p.Ser403Ile	missense_variant	12/12	ENST00000370938.8	NP_001893.2	P32929-1
CTH	NM_001190463.2 linkuse as main transcript	c.1112G>T	p.Ser371Ile	missense_variant	11/11		NP_001177392.1	P32929-3
CTH	NM_153742.5 linkuse as main transcript	c.1076G>T	p.Ser359Ile	missense_variant	11/11		NP_714964.2	P32929-2
CTH	XM_017000416.3 linkuse as main transcript	c.638G>T	p.Ser213Ile	missense_variant	9/9		XP_016855905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CTH	ENST00000370938.8 linkuse as main transcript	c.1208G>T	p.Ser403Ile	missense_variant	12/12	1	NM_001902.6	ENSP00000359976.3	P32929-1
CTH	ENST00000346806.2 linkuse as main transcript	c.1076G>T	p.Ser359Ile	missense_variant	11/11	1		ENSP00000311554.2	P32929-2
CTH	ENST00000411986.6 linkuse as main transcript	c.1112G>T	p.Ser371Ile	missense_variant	11/11	2		ENSP00000413407.2	P32929-3
CTH	ENST00000482383.1 linkuse as main transcript	n.483G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36123

AN:

151884

Hom.:

4984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0994

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.276

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.231

GnomAD3 exomes

AF:

0.285

AC:

71530

AN:

251056

Hom.:

11225

AF XY:

0.282

AC XY:

38218

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0982

Gnomad AMR exome

AF:

0.439

Gnomad ASJ exome

AF:

0.273

Gnomad EAS exome

AF:

0.209

Gnomad SAS exome

AF:

0.242

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.284

AC:

414271

AN:

1456520

Hom.:

61135

Cov.:

AF XY:

0.283

AC XY:

204939

AN XY:

724830

show subpopulations

Gnomad4 AFR exome

AF:

0.0967

Gnomad4 AMR exome

AF:

0.422

Gnomad4 ASJ exome

AF:

0.266

Gnomad4 EAS exome

AF:

0.237

Gnomad4 SAS exome

AF:

0.239

Gnomad4 FIN exome

AF:

0.287

Gnomad4 NFE exome

AF:

0.291

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.238

AC:

36120

AN:

152002

Hom.:

4981

Cov.:

AF XY:

0.238

AC XY:

17677

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0993

Gnomad4 AMR

AF:

0.337

Gnomad4 ASJ

AF:

0.274

Gnomad4 EAS

AF:

0.215

Gnomad4 SAS

AF:

0.232

Gnomad4 FIN

AF:

0.276

Gnomad4 NFE

AF:

0.293

Gnomad4 OTH

AF:

0.228

Alfa

AF:

0.277

Hom.:

13992

Bravo

AF:

0.241

TwinsUK

AF:

0.297

AC:

1100

ALSPAC

AF:

0.276

AC:

1065

ESP6500AA

AF:

0.108

AC:

476

ESP6500EA

AF:

0.304

AC:

2617

ExAC

AF:

0.277

AC:

33636

Asia WGS

AF:

0.219

AC:

760

AN:

3478

EpiCase

AF:

0.276

EpiControl

AF:

0.280

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystathioninuria

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CTH-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Homocysteine level elevated

Other:1

association, no assertion criteria provided

literature only

OMIM

Aug 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.026

.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.00072

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.065

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.23, 0.34

.;B;B

Vest4

0.19

MPC

0.18

ClinPred

0.0026

GERP RS

0.84

Varity_R

0.049

gMVP

0.47

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