chr1-70430388-C-A

Variant names:

• chr1-70430388-C-A
• NM_001902.6:c.718C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001902.6(CTH):​c.718C>A​(p.Gln240Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q240E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CTH NM_001902.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-70430388-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2940.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6	c.718C>A	p.Gln240Lys	missense_variant	Exon 7 of 12	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.622C>A	p.Gln208Lys	missense_variant	Exon 6 of 11		NP_001177392.1
CTH	NM_153742.5	c.586C>A	p.Gln196Lys	missense_variant	Exon 6 of 11		NP_714964.2
CTH	XM_017000416.3	c.148C>A	p.Gln50Lys	missense_variant	Exon 4 of 9		XP_016855905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.718C>A	p.Gln240Lys	missense_variant	Exon 7 of 12	1	NM_001902.6	ENSP00000359976.3
CTH	ENST00000346806.2	c.586C>A	p.Gln196Lys	missense_variant	Exon 6 of 11	1		ENSP00000311554.2
CTH	ENST00000411986.6	c.622C>A	p.Gln208Lys	missense_variant	Exon 6 of 11	2		ENSP00000413407.2
CTH	ENST00000464926.1	n.766C>A		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393214 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 697500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.53e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.93
MutPred		0.74		.;Gain of ubiquitination at Q240 (P = 0.1326);.;
MVP		0.96
MPC		0.71
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-70896071;