21-43065263-C-A

Variant names:

• chr21-43065263-C-A
• rs763835246
• NM_000071.3:c.676G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM5 PP2 PP5_Moderate BP4

The NM_000071.3(CBS):​c.676G>T​(p.Ala226Ser) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A226D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.70
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065262-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2781936.
• 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.
• PP5: Variant 21-43065263-C-A is Pathogenic according to our data. Variant chr21-43065263-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3004170.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39787737). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.676G>T	p.Ala226Ser	missense_variant	Exon 8 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.676G>T	p.Ala226Ser	missense_variant	Exon 8 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.81e-7 AC: 1 AN: 1280734 Hom.: 0 Cov.: 27 AF XY: 0.00000157 AC XY: 1 AN XY: 638702

African (AFR) AF: 0.00 AC: 0 AN: 31498

American (AMR) AF: 0.00 AC: 0 AN: 42880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 955574

Other (OTH) AF: 0.00 AC: 0 AN: 54004

GnomAD4 genome Cov.: 15

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala226 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635102, 15365998, 21520339, 22267502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with CBS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 226 of the CBS protein (p.Ala226Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D;D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.46	N;N;N;N
PhyloP100		2.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.39
MutPred		0.59		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.73
MPC		0.34
ClinPred		0.42	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.63
Mutation Taster		=80/20	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: rs763835246; hg19: chr21-44485373;