rs1555874874

Variant names:

• chr21-43065403-G-A
• rs1555874874
• NM_000071.3:c.650C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43065403-G-A
• chr21-43065403-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PP2 PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.650C>T​(p.Ser217Phe) 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 (★). ClinVar reports functional evidence for this variant: "SCV006071303: The most pronounced variant effect results in <5% activity versus the WT protein, reduced activation in response to S-Adenosylmethionine, and the absence of a correctly assembled tetramer detected by Western blot (Katsushima_2006). PMID:16307898".

• Frequency: Genomes: not found (cov: 5)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.36
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006071303: The most pronounced variant effect results in <5% activity versus the WT protein, reduced activation in response to S-Adenosylmethionine, and the absence of a correctly assembled tetramer detected by Western blot (Katsushima_2006). PMID: 16307898
• 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, 0.991
• PP5: Variant 21-43065403-G-A is Pathogenic according to our data. Variant chr21-43065403-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 557413.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.650C>T	p.Ser217Phe	missense	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.650C>T	p.Ser217Phe	missense	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.650C>T	p.Ser217Phe	missense	Exon 7 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.650C>T	p.Ser217Phe	missense	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.650C>T	p.Ser217Phe	missense	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.650C>T	p.Ser217Phe	missense	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 5

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Classic homocystinuria (1)
1	-	-	Homocystinuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.93		Gain of sheet (P = 0.0344)
MVP		0.94
MPC		1.2
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.91
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs1555874874; hg19: chr21-44485513;