1-70421600-A-T

Variant names:

• chr1-70421600-A-T
• rs886046511
• NM_001902.6:c.381A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001902.6(CTH):​c.381A>T​(p.Glu127Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E127E) has been classified 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: 0.365
• Publications: 0 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: Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13093922).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001902.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	NM_001902.6	MANE Select	c.381A>T	p.Glu127Asp	missense	Exon 4 of 12	NP_001893.2
	CTH	NM_001190463.2		c.285A>T	p.Glu95Asp	missense	Exon 3 of 11	NP_001177392.1	P32929-3
	CTH	NM_153742.5		c.381A>T	p.Glu127Asp	missense	Exon 4 of 11	NP_714964.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	ENST00000370938.8	TSL:1 MANE Select	c.381A>T	p.Glu127Asp	missense	Exon 4 of 12	ENSP00000359976.3	P32929-1
	CTH	ENST00000346806.2	TSL:1	c.381A>T	p.Glu127Asp	missense	Exon 4 of 11	ENSP00000311554.2	P32929-2
	CTH	ENST00000896200.1		c.381A>T	p.Glu127Asp	missense	Exon 5 of 13	ENSP00000566259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251400 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
PhyloP100		0.36
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.24	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.27		Gain of helix (P = 0.132)
MVP		0.73
MPC		0.13
ClinPred		0.088	T
GERP RS		2.1
Varity_R		0.37
gMVP		0.62
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886046511; hg19: chr1-70887283;