NM_001902.6:c.-140A>T

Variant names:

• chr1-70411276-A-T
• rs17131292
• NM_001902.6:c.-140A>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.-140A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0087 in 841,946 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (176 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (90 hom.)
• Consequence: CTH NM_001902.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.485
• Publications: 2 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

ENSG00000304098 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-70411276-A-T is Benign according to our data. Variant chr1-70411276-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 298027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0846 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.-140A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_001893.2
	CTH	NM_001902.6	MANE Select	c.-140A>T		5_prime_UTR	Exon 1 of 12	NP_001893.2
	CTH	NM_001190463.2		c.-140A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001177392.1	P32929-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	ENST00000370938.8	TSL:1 MANE Select	c.-140A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000359976.3	P32929-1
	CTH	ENST00000370938.8	TSL:1 MANE Select	c.-140A>T		5_prime_UTR	Exon 1 of 12	ENSP00000359976.3	P32929-1
	CTH	ENST00000896205.1		c.-140A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000566264.1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3966 AN: 152180 Hom.: 176 Cov.: 33

Gnomad AFR AF: 0.0870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.00485 AC: 3344 AN: 689648 Hom.: 90 Cov.: 9 AF XY: 0.00411 AC XY: 1525 AN XY: 371344

African (AFR) AF: 0.0864 AC: 1619 AN: 18734

American (AMR) AF: 0.00615 AC: 267 AN: 43418

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 553 AN: 21256

East Asian (EAS) AF: 0.00 AC: 0 AN: 36282

South Asian (SAS) AF: 0.000727 AC: 51 AN: 70188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51478

Middle Eastern (MID) AF: 0.0277 AC: 105 AN: 3796

European-Non Finnish (NFE) AF: 0.00104 AC: 424 AN: 409572

Other (OTH) AF: 0.00931 AC: 325 AN: 34924

GnomAD4 genome AF: 0.0261 AC: 3977 AN: 152298 Hom.: 176 Cov.: 33 AF XY: 0.0255 AC XY: 1903 AN XY: 74482

African (AFR) AF: 0.0869 AC: 3612 AN: 41546

American (AMR) AF: 0.0104 AC: 159 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68038

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0152 Hom.: 9

Bravo AF: 0.0296

Asia WGS AF: 0.00577 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cystathioninuria (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		0.48
PromoterAI		0.030	Neutral
Mutation Taster		=300/0	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: rs17131292; hg19: chr1-70876959;