rs12723350

Variant names:

• chr1-70422418-T-C
• rs12723350
• NM_001902.6:c.456+743T>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.456+743T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 152,288 control chromosomes in the GnomAD database, including 222 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 0.048 (222 hom., cov: 32)
• Consequence: CTH NM_001902.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.605
• Publications: 4 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6	c.456+743T>C		intron_variant	Intron 4 of 11	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.360+743T>C		intron_variant	Intron 3 of 10		NP_001177392.1
CTH	NM_153742.5	c.456+743T>C		intron_variant	Intron 4 of 10		NP_714964.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.456+743T>C		intron_variant	Intron 4 of 11	1	NM_001902.6	ENSP00000359976.3
CTH	ENST00000346806.2	c.456+743T>C		intron_variant	Intron 4 of 10	1		ENSP00000311554.2
CTH	ENST00000411986.6	c.360+743T>C		intron_variant	Intron 3 of 10	2		ENSP00000413407.2
CTH	ENST00000464926.1	n.504+743T>C		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 7271 AN: 152170 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0737

Gnomad OTH AF: 0.0521

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

GnomAD4 genome AF: 0.0477 AC: 7271 AN: 152288 Hom.: 222 Cov.: 32 AF XY: 0.0451 AC XY: 3358 AN XY: 74466

African (AFR) AF: 0.0125 AC: 521 AN: 41572

American (AMR) AF: 0.0507 AC: 775 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4824

European-Finnish (FIN) AF: 0.0415 AC: 440 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0737 AC: 5014 AN: 68010

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0620 Hom.: 475

Bravo AF: 0.0470

Asia WGS AF: 0.00895 AC: 31 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	17
DANN	Benign	0.75
PhyloP100		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs12723350; hg19: chr1-70888101;