rs763290176

Variant names:

• chr21-43063899-C-T
• rs763290176
• NM_000071.3:c.828+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000071.3(CBS):​c.828+1G>A variant causes a splice donor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.0000067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.82
• 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 21-43063899-C-T is Pathogenic according to our data. Variant chr21-43063899-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556952.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.828+1G>A		splice_donor intron	N/A	NP_000062.1
	CBS	NM_001178008.3		c.828+1G>A		splice_donor intron	N/A	NP_001171479.1
	CBS	NM_001178009.3		c.828+1G>A		splice_donor intron	N/A	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.828+1G>A		splice_donor intron	N/A	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.828+1G>A		splice_donor intron	N/A	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.828+1G>A		splice_donor intron	N/A	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD2 exomes AF: 0.00000808 AC: 2 AN: 247508 AF XY: 0.0000149

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000671 AC: 1 AN: 149054 Hom.: 0 Cov.: 0 AF XY: 0.0000125 AC XY: 1 AN XY: 80174

African (AFR) AF: 0.00 AC: 0 AN: 5150

American (AMR) AF: 0.00 AC: 0 AN: 9730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3558

East Asian (EAS) AF: 0.00 AC: 0 AN: 16460

South Asian (SAS) AF: 0.00 AC: 0 AN: 23536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 586

European-Non Finnish (NFE) AF: 0.0000135 AC: 1 AN: 73908

Other (OTH) AF: 0.00 AC: 0 AN: 7836

GnomAD4 genome Cov.: 4

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Classic homocystinuria (5)
2	-	-	not provided (2)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.8
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Other links and lift over

dbSNP: rs763290176; hg19: chr21-44484009;