1-70439117-G-T

Variant names:

• chr1-70439117-G-T
• rs1021737
• NM_001902.6:c.1208G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.0840
• Publications: 65 publications found

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: ClinGen, Ambry Genetics, Orphanet

ENSG00000306600 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CTH	NM_001902.6	c.1208G>T	p.Ser403Ile	missense_variant	Exon 12 of 12	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.1112G>T	p.Ser371Ile	missense_variant	Exon 11 of 11		NP_001177392.1
CTH	NM_153742.5	c.1076G>T	p.Ser359Ile	missense_variant	Exon 11 of 11		NP_714964.2
CTH	XM_017000416.3	c.638G>T	p.Ser213Ile	missense_variant	Exon 9 of 9		XP_016855905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.1208G>T	p.Ser403Ile	missense_variant	Exon 12 of 12	1	NM_001902.6	ENSP00000359976.3

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36123 AN: 151884 Hom.: 4984 Cov.: 31

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

GnomAD2 exomes AF: 0.285 AC: 71530 AN: 251056 AF XY: 0.282

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 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.: 31 AF XY: 0.283 AC XY: 204939 AN XY: 724830

African (AFR) AF: 0.0967 AC: 3232 AN: 33426

American (AMR) AF: 0.422 AC: 18868 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6941 AN: 26098

East Asian (EAS) AF: 0.237 AC: 9402 AN: 39656

South Asian (SAS) AF: 0.239 AC: 20591 AN: 86158

European-Finnish (FIN) AF: 0.287 AC: 15329 AN: 53386

Middle Eastern (MID) AF: 0.211 AC: 1214 AN: 5760

European-Non Finnish (NFE) AF: 0.291 AC: 322380 AN: 1107136

Other (OTH) AF: 0.271 AC: 16314 AN: 60196

GnomAD4 genome AF: 0.238 AC: 36120 AN: 152002 Hom.: 4981 Cov.: 31 AF XY: 0.238 AC XY: 17677 AN XY: 74280

African (AFR) AF: 0.0993 AC: 4120 AN: 41492

American (AMR) AF: 0.337 AC: 5140 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 949 AN: 3462

East Asian (EAS) AF: 0.215 AC: 1111 AN: 5166

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4808

European-Finnish (FIN) AF: 0.276 AC: 2910 AN: 10554

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19941 AN: 67946

Other (OTH) AF: 0.228 AC: 480 AN: 2106

Alfa AF: 0.270 Hom.: 19918

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystathioninuria Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CTH-related disorder Benign:1

Aug 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Homocysteine level elevated Other:1

Apr 02, 2025

OMIM

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.026	.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.00072	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N;.
PhyloP100		0.084
PrimateAI	Benign	0.33	T
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	T
GERP RS		0.84
Varity_R		0.049
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

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: rs1021737; hg19: chr1-70904800; COSMIC: COSV61007955;