NM_000071.3:c.904G>A

Variant names:

• chr21-43063003-C-T
• rs779270933
• NM_000071.3:c.904G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PP2 PP3_Strong PP5

The NM_000071.3(CBS):​c.904G>A​(p.Glu302Lys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002051128: Several publications report experimental evidence evaluating an impact on protein function (example, deFranchis_1999, Kozich_2010, Mayfield_2012). The most pronounced variant effect results in 4.9% of normal CBS enzyme activity when expressed in Ecoli extracts and a shorter than expected subunit size by western blot analysis suggestive of partial degradation of the mutant enzyme (deFranchis_1999), inhibited by AdoHcy and not activated by AdoMet (Kozich_2010), and a nonfunctional outcome in yeast as measured by ortholog replacement in Saccharomyces cerevisiae (Mayfield_2012)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E302E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.85
• Publications: 10 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002051128: Several publications report experimental evidence evaluating an impact on protein function (example, deFranchis_1999, Kozich_2010, Mayfield_2012). The most pronounced variant effect results in 4.9% of normal CBS enzyme activity when expressed in Ecoli extracts and a shorter than expected subunit size by western blot analysis suggestive of partial degradation of the mutant enzyme (deFranchis_1999), inhibited by AdoHcy and not activated by AdoMet (Kozich_2010), and a nonfunctional outcome in yeast as measured by ortholog replacement in Saccharomyces cerevisiae (Mayfield_2012).; SCV000769924: Experimental studies have shown that this missense change affects CBS function (PMID: 10338090, 20506325, 22267502).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 21-43063003-C-T is Pathogenic according to our data. Variant chr21-43063003-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496864.

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.904G>A	p.Glu302Lys	missense	Exon 10 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.904G>A	p.Glu302Lys	missense	Exon 10 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.904G>A	p.Glu302Lys	missense	Exon 10 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.904G>A	p.Glu302Lys	missense	Exon 10 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.904G>A	p.Glu302Lys	missense	Exon 10 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.904G>A	p.Glu302Lys	missense	Exon 10 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251416 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Classic homocystinuria (1)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	-0.97	N
PhyloP100		6.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.71
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.41	B
Vest4		0.93
MutPred		0.81		Gain of methylation at E302 (P = 0.0082)
MVP		0.72
MPC		0.62
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs779270933; hg19: chr21-44483113;