1-70421416-A-G

Variant names:

• chr1-70421416-A-G
• rs672203
• NM_001902.6:c.347-150A>G

Variant summary

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

The NM_001902.6(CTH):​c.347-150A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 795,714 control chromosomes in the GnomAD database, including 47,884 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 0.35 (9370 hom., cov: 32)
  • Exomes 𝑓: 0.34 (38514 hom.)
• Consequence: CTH NM_001902.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19
• Publications: 14 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6	c.347-150A>G		intron_variant	Intron 3 of 11	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.251-150A>G		intron_variant	Intron 2 of 10		NP_001177392.1
CTH	NM_153742.5	c.347-150A>G		intron_variant	Intron 3 of 10		NP_714964.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.347-150A>G		intron_variant	Intron 3 of 11	1	NM_001902.6	ENSP00000359976.3
CTH	ENST00000346806.2	c.347-150A>G		intron_variant	Intron 3 of 10	1		ENSP00000311554.2
CTH	ENST00000411986.6	c.251-150A>G		intron_variant	Intron 2 of 10	2		ENSP00000413407.2
CTH	ENST00000464926.1	n.395-150A>G		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52770 AN: 151942 Hom.: 9367 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.340 AC: 219118 AN: 643654 Hom.: 38514 AF XY: 0.340 AC XY: 115360 AN XY: 339654

African (AFR) AF: 0.339 AC: 5468 AN: 16130

American (AMR) AF: 0.220 AC: 6462 AN: 29426

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 6726 AN: 19006

East Asian (EAS) AF: 0.234 AC: 7458 AN: 31900

South Asian (SAS) AF: 0.267 AC: 15603 AN: 58356

European-Finnish (FIN) AF: 0.377 AC: 16028 AN: 42534

Middle Eastern (MID) AF: 0.402 AC: 984 AN: 2450

European-Non Finnish (NFE) AF: 0.363 AC: 149225 AN: 411162

Other (OTH) AF: 0.342 AC: 11164 AN: 32690

GnomAD4 genome AF: 0.347 AC: 52785 AN: 152060 Hom.: 9370 Cov.: 32 AF XY: 0.344 AC XY: 25595 AN XY: 74332

African (AFR) AF: 0.348 AC: 14444 AN: 41486

American (AMR) AF: 0.266 AC: 4062 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3464

East Asian (EAS) AF: 0.236 AC: 1222 AN: 5172

South Asian (SAS) AF: 0.265 AC: 1279 AN: 4826

European-Finnish (FIN) AF: 0.396 AC: 4183 AN: 10566

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25207 AN: 67948

Other (OTH) AF: 0.347 AC: 733 AN: 2112

Alfa AF: 0.357 Hom.: 22142

Bravo AF: 0.336

Asia WGS AF: 0.207 AC: 716 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.8
DANN	Benign	0.60
PhyloP100		3.2
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: rs672203; hg19: chr1-70887099; COSMIC: COSV61009775;