Genetic Variant CTH:c.346+125A>G (chr1-70418157-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001902.6(CTH):c.346+125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,157,582 control chromosomes in the GnomAD database, including 331,197 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.77 ( 44912 hom., cov: 32)

Exomes 𝑓: 0.75 ( 286285 hom. )

Consequence

CTH
NM_001902.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.50

Publications

14 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
CTH	NM_001902.6	MANE Select	c.346+125A>G	intron	N/A	NP_001893.2
CTH	NM_001190463.2		c.250+2120A>G	intron	N/A	NP_001177392.1	P32929-3
CTH	NM_153742.5		c.346+125A>G	intron	N/A	NP_714964.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CTH	ENST00000370938.8	TSL:1 MANE Select	c.346+125A>G	intron	N/A	ENSP00000359976.3	P32929-1
CTH	ENST00000346806.2	TSL:1	c.346+125A>G	intron	N/A	ENSP00000311554.2	P32929-2
CTH	ENST00000896200.1		c.346+125A>G	intron	N/A	ENSP00000566259.1

Frequencies

GnomAD3 genomes

AF:

0.767

AC:

116611

AN:

151992

Hom.:

44862

Cov.:

show subpopulations

Gnomad AFR

AF:

0.793

Gnomad AMI

AF:

0.786

Gnomad AMR

AF:

0.822

Gnomad ASJ

AF:

0.729

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.800

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.739

Gnomad OTH

AF:

0.761

GnomAD4 exome

AF:

0.754

AC:

757942

AN:

1005472

Hom.:

286285

AF XY:

0.754

AC XY:

386354

AN XY:

512178

show subpopulations

African (AFR)

AF:

0.794

AC:

18719

AN:

23580

American (AMR)

AF:

0.859

AC:

29562

AN:

34408

Ashkenazi Jewish (ASJ)

AF:

0.724

AC:

16113

AN:

22242

East Asian (EAS)

AF:

0.813

AC:

27379

AN:

33682

South Asian (SAS)

AF:

0.793

AC:

55317

AN:

69754

European-Finnish (FIN)

AF:

0.738

AC:

30394

AN:

41158

Middle Eastern (MID)

AF:

0.741

AC:

2732

AN:

3688

European-Non Finnish (NFE)

AF:

0.743

AC:

543588

AN:

731962

Other (OTH)

AF:

0.759

AC:

34138

AN:

44998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

9316

18632

27948

37264

46580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11340

22680

34020

45360

56700

<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:

0.767

AC:

116717

AN:

152110

Hom.:

44912

Cov.:

AF XY:

0.769

AC XY:

57186

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.793

AC:

32912

AN:

41492

American (AMR)

AF:

0.822

AC:

12561

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.729

AC:

2527

AN:

3466

East Asian (EAS)

AF:

0.820

AC:

4244

AN:

5174

South Asian (SAS)

AF:

0.799

AC:

3859

AN:

4830

European-Finnish (FIN)

AF:

0.738

AC:

7795

AN:

10564

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.739

AC:

50260

AN:

67984

Other (OTH)

AF:

0.763

AC:

1609

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1424

2847

4271

5694

7118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<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:

0.751

Hom.:

143009

Bravo

AF:

0.776

Asia WGS

AF:

0.804

AC:

2797

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.021

(source)

DANN

Benign

0.66

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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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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