21-43063074-A-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000071.3(CBS):​c.833T>C​(p.Ile278Thr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I278S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:37 U:1 O:2
• Conservation: PhyloP100: 8.10
• Publications: 257 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 13 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.868
• PP5: Variant 21-43063074-A-G is Pathogenic according to our data. 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.

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.833T>C	p.Ile278Thr	missense	Exon 10 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.833T>C	p.Ile278Thr	missense	Exon 10 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.833T>C	p.Ile278Thr	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.833T>C	p.Ile278Thr	missense	Exon 10 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.833T>C	p.Ile278Thr	missense	Exon 10 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.833T>C	p.Ile278Thr	missense	Exon 10 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.0129 Hom.: 2

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00108 AC: 131

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Classic homocystinuria (17)
13	-	-	not provided (13)
2	-	-	Homocystinuria (2)
2	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (2)
1	-	-	Connective tissue disorder (1)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria, pyridoxine-responsive (1)
-	1	-	Intellectual disability (1)
1	-	-	See cases (1)
1	-	-	Thoracic aortic aneurysm or dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.049	D
Polyphen		0.97	D
Vest4		0.84
MVP		0.82
MPC		1.2
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.85
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs5742905; hg19: chr21-44483184; COSMIC: COSV61442824; COSMIC: COSV61442824;