rs758447354
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000071.3(CBS):c.982G>A(p.Asp328Asn) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D328D) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 0)
Consequence
CBS
NM_000071.3 missense
NM_000071.3 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 6.85
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000071.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
?
Variant 21-43062368-C-T is Pathogenic according to our data. Variant chr21-43062368-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550653.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.982G>A | p.Asp328Asn | missense_variant | 11/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.982G>A | p.Asp328Asn | missense_variant | 11/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
GnomAD3 genomes
?
Cov.:
0
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250848Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135748
GnomAD3 exomes
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2
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250848
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135748
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GnomAD4 exome Cov.: 0
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GnomAD4 genome ? Cov.: 0
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ExAC
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EpiCase
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 08, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25939784) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 25, 2018 | The CBS c.982G>A; p.Asp328Asn variant (rs758447354) has been described in the compound heterozygous state in one individual with homocystinuria due to cystathionine beta-synthase deficiency (Silao 2015) and is observed in the general population at a low overall frequency of 0.0008% (2/245840 alleles) in the Genome Aggregation Database. The aspartic acid at codon 328 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Silao C et al. Novel cystathionine beta-synthase gene mutations in a Filipino patient with classic homocystinuria. Pediatr Int. 2015 Oct;57(5):884-7. - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 21, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 328 of the CBS protein (p.Asp328Asn). This variant is present in population databases (rs758447354, gnomAD 0.002%). This missense change has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 25939784, 33057012). ClinVar contains an entry for this variant (Variation ID: 550653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function. For these reasons, this variant has been classified as Pathogenic. - |
Homocystinuria Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2023 | Variant summary: CBS c.982G>A (p.Asp328Asn) results in a conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250848 control chromosomes (gnomAD). c.982G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with classic homocystinuria (Silao_2015, Kaur_2020, Alsharhan_2021), and in one case with congenital ectopia lentis (Chen_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at