1-70430302-G-C

Position:

• chr1-70430302-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001902.6(CTH):​c.647-15G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,493,734 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (15 hom.)
• Consequence: CTH NM_001902.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00748 (1138/152092) while in subpopulation AFR AF= 0.0254 (1056/41518). AF 95% confidence interval is 0.0242. There are 17 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTH	NM_001902.6	c.647-15G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370938.8
CTH	NM_001190463.2	c.551-15G>C		splice_polypyrimidine_tract_variant, intron_variant
CTH	NM_153742.5	c.515-15G>C		splice_polypyrimidine_tract_variant, intron_variant
CTH	XM_017000416.3	c.77-15G>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTH	ENST00000370938.8	c.647-15G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001902.6	P1
CTH	ENST00000346806.2	c.515-15G>C		splice_polypyrimidine_tract_variant, intron_variant		1
CTH	ENST00000411986.6	c.551-15G>C		splice_polypyrimidine_tract_variant, intron_variant		2
CTH	ENST00000464926.1	n.695-15G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1138 AN: 151974 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00768

GnomAD3 exomes AF: 0.00201 AC: 502 AN: 250098 Hom.: 7 AF XY: 0.00149 AC XY: 202 AN XY: 135206

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000744 AC: 998 AN: 1341642 Hom.: 15 Cov.: 22 AF XY: 0.000664 AC XY: 448 AN XY: 674922

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00748 AC: 1138 AN: 152092 Hom.: 17 Cov.: 32 AF XY: 0.00725 AC XY: 539 AN XY: 74368

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00760

Alfa AF: 0.000986 Hom.: 0

Bravo AF: 0.00824

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystathioninuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs140590694; hg19: chr1-70895985;