chr21-43063074-A-C

Variant names:

• chr21-43063074-A-C
• rs5742905
• NM_000071.3:c.833T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM5 PP2 PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.833T>G​(p.Ile278Ser) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. I278T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.10
• 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 9 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43063074-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 21-43063074-A-C is Pathogenic according to our data. Variant chr21-43063074-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3075863.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.833T>G	p.Ile278Ser	missense_variant	Exon 10 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.833T>G	p.Ile278Ser	missense_variant	Exon 10 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Classic homocystinuria Pathogenic:1

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile278Ser variant in CBS has been reported in one individual with classic homocystinuria in compound heterozygosity with a pathogenic variant. (Cozar 2011 PMID 21520339). The variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Ile278Thr) has been identified in individuals with homocystinuria and is classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive classic homocystinuria. ACMG/AMP criteria applied: PM3, PM5, PP3, PM2_Supporting. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;.;.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;H;H
PhyloP100		8.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.95
MutPred		0.84		Loss of stability (P = 0.0057);Loss of stability (P = 0.0057);Loss of stability (P = 0.0057);Loss of stability (P = 0.0057);
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -1

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

Other links and lift over

dbSNP: rs5742905; hg19: chr21-44483184;