chr1-70424340-G-C

Variant names:

• chr1-70424340-G-C
• rs148637178
• NM_001902.6:c.512G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001902.6(CTH):​c.512G>C​(p.Gly171Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,060 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CTH NM_001902.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.87

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011099964).
• BP6: Variant 1-70424340-G-C is Benign according to our data. Variant chr1-70424340-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3498163.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6	c.512G>C	p.Gly171Ala	missense_variant	Exon 5 of 12	ENST00000370938.8	NP_001893.2
CTH	NM_001190463.2	c.416G>C	p.Gly139Ala	missense_variant	Exon 4 of 11		NP_001177392.1
CTH	XM_017000416.3	c.-59G>C		5_prime_UTR_variant	Exon 2 of 9		XP_016855905.1
CTH	NM_153742.5	c.456+2665G>C		intron_variant	Intron 4 of 10		NP_714964.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTH	ENST00000370938.8	c.512G>C	p.Gly171Ala	missense_variant	Exon 5 of 12	1	NM_001902.6	ENSP00000359976.3
CTH	ENST00000346806.2	c.456+2665G>C		intron_variant	Intron 4 of 10	1		ENSP00000311554.2
CTH	ENST00000411986.6	c.416G>C	p.Gly139Ala	missense_variant	Exon 4 of 11	2		ENSP00000413407.2
CTH	ENST00000464926.1	n.560G>C		non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000278 AC: 70 AN: 251444 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135888

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70 AN XY: 727220

Gnomad4 AFR exome AF: 0.00475

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74424

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.00139

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.090
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.31
MVP		0.57
MPC		0.15
ClinPred		0.0060	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.55

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: rs148637178; hg19: chr1-70890023;