Genetic Variant ENSG00000306600:n.181-6037A>C (chr1-70439991-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000819612.1(ENSG00000306600):n.181-6037A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,046 control chromosomes in the GnomAD database, including 4,840 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 0.23 ( 4838 hom., cov: 32)

Exomes 𝑓: 0.42 ( 2 hom. )

Consequence

ENSG00000306600
ENST00000819612.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0680

Publications

6 publications found

Variant links:

Genes affected

ENSG00000306600 (HGNC:):

ENSG00000306600 links:

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

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=-0.83).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CTH	NM_001902.6 link	c.*864T>G	downstream_gene_variant	ENST00000370938.8	NP_001893.2	P32929-1
CTH	NM_001190463.2 link	c.*864T>G	downstream_gene_variant		NP_001177392.1	P32929-3
CTH	NM_153742.5 link	c.*864T>G	downstream_gene_variant		NP_714964.2	P32929-2
CTH	XM_017000416.3 link	c.*864T>G	downstream_gene_variant		XP_016855905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8 link	c.*864T>G		downstream_gene_variant		1	NM_001902.6	ENSP00000359976.3		P32929-1

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34223

AN:

151916

Hom.:

4841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0538

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.336

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.272

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.230

GnomAD4 exome

AF:

0.417

AC:

AN:

Hom.:

AF XY:

0.417

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.225

AC:

34214

AN:

152034

Hom.:

4838

Cov.:

AF XY:

0.226

AC XY:

16783

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0537

AC:

2230

AN:

41532

American (AMR)

AF:

0.336

AC:

5126

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1010

AN:

3468

East Asian (EAS)

AF:

0.220

AC:

1133

AN:

5156

South Asian (SAS)

AF:

0.241

AC:

1161

AN:

4810

European-Finnish (FIN)

AF:

0.272

AC:

2859

AN:

10526

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.293

AC:

19923

AN:

67954

Other (OTH)

AF:

0.227

AC:

479

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1268

2536

3803

5071

6339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.265

Hom.:

15256

Bravo

AF:

0.227

Asia WGS

AF:

0.228

AC:

793

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.9

(source)

DANN

Benign

0.75

PhyloP100

-0.068

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over