rs681475

Variant names:

• chr1-70415034-T-C
• rs681475
• NM_001902.6:c.169-922T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001902.6(CTH):​c.169-922T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 151,974 control chromosomes in the GnomAD database, including 31,547 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 0.64 (31547 hom., cov: 31)
• Consequence: CTH NM_001902.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 10 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: Orphanet, Ambry Genetics, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.667 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	NM_001902.6	MANE Select	c.169-922T>C		intron	N/A	NP_001893.2
	CTH	NM_001190463.2		c.169-922T>C		intron	N/A	NP_001177392.1	P32929-3
	CTH	NM_153742.5		c.169-922T>C		intron	N/A	NP_714964.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	ENST00000370938.8	TSL:1 MANE Select	c.169-922T>C		intron	N/A	ENSP00000359976.3	P32929-1
	CTH	ENST00000346806.2	TSL:1	c.169-922T>C		intron	N/A	ENSP00000311554.2	P32929-2
	CTH	ENST00000896200.1		c.169-922T>C		intron	N/A	ENSP00000566259.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97478 AN: 151856 Hom.: 31527 Cov.: 31

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.639

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.642 AC: 97532 AN: 151974 Hom.: 31547 Cov.: 31 AF XY: 0.640 AC XY: 47538 AN XY: 74284

African (AFR) AF: 0.599 AC: 24805 AN: 41430

American (AMR) AF: 0.651 AC: 9951 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2320 AN: 3472

East Asian (EAS) AF: 0.518 AC: 2671 AN: 5152

South Asian (SAS) AF: 0.628 AC: 3027 AN: 4820

European-Finnish (FIN) AF: 0.653 AC: 6891 AN: 10560

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45688 AN: 67954

Other (OTH) AF: 0.633 AC: 1333 AN: 2106

Alfa AF: 0.662 Hom.: 63956

Bravo AF: 0.642

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		0.15
Mutation Taster		=100/0	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: rs681475; hg19: chr1-70880717;