rs886039146

Variant names:

• chr21-43058834-C-T
• rs886039146
• NM_000071.3:c.1358G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP2 PP3_Strong

The ENST00000398165.8(CBS):​c.1358G>A​(p.Gly453Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G453R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.50
• Publications: 2 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000398165.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43058835-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064787.Status of the report is criteria_provided_single_submitter, 1 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398165.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1358G>A	p.Gly453Glu	missense splice_region	Exon 14 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00 AC: 0 AN: 161528 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Classic homocystinuria (3)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.81
Sift	Benign	0.041	D
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.76		Loss of catalytic residue at A452 (P = 0.0367)
MVP		0.91
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		0.040	Neutral
Varity_R		0.86
gMVP		0.88
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 0

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

Other links and lift over

dbSNP: rs886039146; hg19: chr21-44478944;