21-43065263-C-T

Variant names:

• chr21-43065263-C-T
• rs763835246
• NM_000071.3:c.676G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP5_Very_Strong

The NM_000071.3(CBS):​c.676G>A​(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A226D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.70
• Publications: 13 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.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065262-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2781936.
• 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.
• PP5: Variant 21-43065263-C-T is Pathogenic according to our data. Variant chr21-43065263-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 370382.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.676G>A	p.Ala226Thr	missense	Exon 8 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.676G>A	p.Ala226Thr	missense	Exon 8 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.676G>A	p.Ala226Thr	missense	Exon 8 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.676G>A	p.Ala226Thr	missense	Exon 8 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.676G>A	p.Ala226Thr	missense	Exon 8 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.676G>A	p.Ala226Thr	missense	Exon 8 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.81e-7 AC: 1 AN: 1280734 Hom.: 0 Cov.: 27 AF XY: 0.00000157 AC XY: 1 AN XY: 638702

African (AFR) AF: 0.00 AC: 0 AN: 31498

American (AMR) AF: 0.00 AC: 0 AN: 42880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 80082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5134

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 955574

Other (OTH) AF: 0.00 AC: 0 AN: 54004

GnomAD4 genome Cov.: 15

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Classic homocystinuria (4)
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	Benign	0.10
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.71	N
PhyloP100		2.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.020	D
Sift4G	Benign	0.074	T
Polyphen		0.10	B
Vest4		0.41
MutPred		0.82		Gain of glycosylation at A226 (P = 0.0447)
MVP		0.76
MPC		0.39
ClinPred		0.59	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.68
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs763835246; hg19: chr21-44485373;