rs1021737

Positions:

• chr1-70439117-G-A
• chr1-70439117-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001902.6(CTH):​c.1208G>A​(p.Ser403Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,200 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTH NM_001902.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057379633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTH	NM_001902.6	c.1208G>A	p.Ser403Asn	missense_variant	12/12	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.1112G>A	p.Ser371Asn	missense_variant	11/11		NP_001177392.1
CTH	NM_153742.5	c.1076G>A	p.Ser359Asn	missense_variant	11/11		NP_714964.2
CTH	XM_017000416.3	c.638G>A	p.Ser213Asn	missense_variant	9/9		XP_016855905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.1208G>A	p.Ser403Asn	missense_variant	12/12	1	NM_001902.6	ENSP00000359976	P1
CTH	ENST00000346806.2	c.1076G>A	p.Ser359Asn	missense_variant	11/11	1		ENSP00000311554
CTH	ENST00000411986.6	c.1112G>A	p.Ser371Asn	missense_variant	11/11	2		ENSP00000413407
CTH	ENST00000482383.1	n.483G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459200 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726084

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.61
DEOGEN2	Benign	0.019	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.082
MutPred		0.093		.;Loss of phosphorylation at S403 (P = 0.0093);.;
MVP		0.46
MPC		0.13
ClinPred		0.059	T
GERP RS		0.84
Varity_R		0.037
gMVP		0.29

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: rs1021737; hg19: chr1-70904800;