21-43068528-G-C

Variant names:

• chr21-43068528-G-C
• rs749697783
• NM_000071.3:c.297C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000071.3(CBS):​c.297C>G​(p.Phe99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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: not found (cov: 6)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.557
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 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=0.0851098).

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.297C>G	p.Phe99Leu	missense	Exon 4 of 17	NP_000062.1
	CBS	NM_001178008.3		c.297C>G	p.Phe99Leu	missense	Exon 4 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.297C>G	p.Phe99Leu	missense	Exon 4 of 18	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.297C>G	p.Phe99Leu	missense	Exon 4 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.297C>G	p.Phe99Leu	missense	Exon 4 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.297C>G	p.Phe99Leu	missense	Exon 4 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 6

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	0.16
DANN	Benign	0.68
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.085	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.41	N
PhyloP100		0.56
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.29
Sift	Benign	0.75	T
Sift4G	Benign	0.72	T
Polyphen		0.0030	B
Vest4		0.46
MutPred		0.30		Loss of methylation at K98 (P = 0.0284)
MVP		0.25
MPC		0.41
ClinPred		0.044	T
GERP RS		-8.9
Varity_R		0.23
gMVP		0.80
Mutation Taster		=83/17	polymorphism

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: rs749697783; hg19: chr21-44488638;