chr1-70411430-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001902.6(CTH):​c.15C>A​(p.Asp5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,018 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: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CTH
NM_001902.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.227
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.008207053).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CTHNM_001902.6 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/12 ENST00000370938.8
CTHNM_001190463.2 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/11
CTHNM_153742.5 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTHENST00000370938.8 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/121 NM_001902.6 P1P32929-1
CTHENST00000346806.2 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/111 P32929-2
CTHENST00000411986.6 linkuse as main transcriptc.15C>A p.Asp5Glu missense_variant 1/112 P32929-3
CTHENST00000464926.1 linkuse as main transcriptn.159C>A non_coding_transcript_exon_variant 1/65

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000199
AC:
50
AN:
251486
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000193
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000214
AC:
313
AN:
1461710
Hom.:
0
Cov.:
31
AF XY:
0.000187
AC XY:
136
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000827
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:
0.000237
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000335
AC:
51
AN:
152308
Hom.:
0
Cov.:
33
AF XY:
0.000363
AC XY:
27
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00163
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.000334
Hom.:
0
Bravo
AF:
0.000608
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000198
AC:
24
EpiCase
AF:
0.00
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystathioninuria Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The c.15C>A (p.D5E) alteration is located in exon 1 (coding exon 1) of the CTH gene. This alteration results from a C to A substitution at nucleotide position 15, causing the aspartic acid (D) at amino acid position 5 to be replaced by a glutamic acid (E). 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
0.088
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
4.4
DANN
Benign
0.72
DEOGEN2
Benign
0.026
.;T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.50
T;T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.0082
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L;L
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.34
N;N;N
REVEL
Benign
0.055
Sift
Benign
0.34
T;T;T
Sift4G
Benign
0.54
T;T;T
Polyphen
0.0, 0.0010
.;B;B
Vest4
0.065
MutPred
0.35
Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);
MVP
0.23
MPC
0.13
ClinPred
0.029
T
GERP RS
-0.49
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.040
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143859234; hg19: chr1-70877113; API