rs112029370

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000071.3(CBS):​c.296T>C​(p.Phe99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F99Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000051 ( 0 hom., cov: 6)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.670

Publications

0 publications found
Variant links:
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]
CBS Gene-Disease associations (from GenCC):
  • classic homocystinuria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000071.3
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.
BP4
Computational evidence support a benign effect (MetaRNN=0.19022945).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBSNM_000071.3 linkc.296T>C p.Phe99Ser missense_variant Exon 4 of 17 ENST00000398165.8 NP_000062.1 P35520-1Q9NTF0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBSENST00000398165.8 linkc.296T>C p.Phe99Ser missense_variant Exon 4 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
AF:
0.0000257
AC:
1
AN:
38986
Hom.:
0
Cov.:
6
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000548
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000293
AC:
1
AN:
340968
Hom.:
0
Cov.:
0
AF XY:
0.00000545
AC XY:
1
AN XY:
183546
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
8940
American (AMR)
AF:
0.00
AC:
0
AN:
22662
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
11414
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26726
South Asian (SAS)
AF:
0.00
AC:
0
AN:
43508
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
20598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1440
European-Non Finnish (NFE)
AF:
0.00000535
AC:
1
AN:
186800
Other (OTH)
AF:
0.00
AC:
0
AN:
18880
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000512
AC:
2
AN:
39074
Hom.:
0
Cov.:
6
AF XY:
0.0000556
AC XY:
1
AN XY:
17998
show subpopulations
African (AFR)
AF:
0.000122
AC:
1
AN:
8198
American (AMR)
AF:
0.00
AC:
0
AN:
5300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
1144
East Asian (EAS)
AF:
0.00
AC:
0
AN:
1766
South Asian (SAS)
AF:
0.00
AC:
0
AN:
990
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
2424
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
96
European-Non Finnish (NFE)
AF:
0.0000548
AC:
1
AN:
18260
Other (OTH)
AF:
0.00
AC:
0
AN:
512
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1
Apr 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 99 of the CBS protein (p.Phe99Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CBS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
21
DANN
Benign
0.86
DEOGEN2
Pathogenic
0.88
D;D;D;D;.
Eigen
Benign
-0.99
Eigen_PC
Benign
-1.0
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.90
.;.;.;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.19
T;T;T;T;T
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
0.36
N;N;N;N;.
PhyloP100
0.67
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.3
N;N;N;N;D
REVEL
Uncertain
0.38
Sift
Benign
0.34
T;T;T;T;T
Sift4G
Benign
0.32
T;T;T;T;T
Polyphen
0.087
B;B;B;B;.
Vest4
0.53
MutPred
0.53
Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);
MVP
0.46
MPC
0.65
ClinPred
0.48
T
GERP RS
-3.7
Varity_R
0.22
gMVP
0.86
Mutation Taster
=80/20
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs112029370; hg19: chr21-44488639; API