1-70430370-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001902.6(CTH):c.700A>G(p.Asn234Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,439,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTH NM_001902.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18697992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTH	NM_001902.6	c.700A>G	p.Asn234Asp	missense_variant	7/12	ENST00000370938.8
CTH	NM_001190463.2	c.604A>G	p.Asn202Asp	missense_variant	6/11
CTH	NM_153742.5	c.568A>G	p.Asn190Asp	missense_variant	6/11
CTH	XM_017000416.3	c.130A>G	p.Asn44Asp	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTH	ENST00000370938.8	c.700A>G	p.Asn234Asp	missense_variant	7/12	1	NM_001902.6	P1
CTH	ENST00000346806.2	c.568A>G	p.Asn190Asp	missense_variant	6/11	1
CTH	ENST00000411986.6	c.604A>G	p.Asn202Asp	missense_variant	6/11	2
CTH	ENST00000464926.1	n.748A>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439344 Hom.: 0 Cov.: 26 AF XY: 0.00000279 AC XY: 2 AN XY: 717590

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: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The c.700A>G (p.N234D) alteration is located in exon 7 (coding exon 7) of the CTH gene. This alteration results from a A to G substitution at nucleotide position 700, causing the asparagine (N) at amino acid position 234 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.091
Dann	Benign	0.68
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.86	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.34	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.32
MutPred		0.48		.;Loss of methylation at R237 (P = 0.0924);.;
MVP		0.61
MPC		0.16
ClinPred		0.073	T
GERP RS		-7.0
Varity_R		0.065
gMVP		0.34

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: rs1684437867; hg19: chr1-70896053;