rs1555869934

Variant names:

• chr21-43053931-GGT-G
• rs1555869934
• NM_000071.3:c.1603_1604delAC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The ENST00000398165.8(CBS):​c.1603_1604delAC​(p.Thr535ArgfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T535T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.032 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 21-43053931-GGT-G is Pathogenic according to our data. Variant chr21-43053931-GGT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551171.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 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.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1603_1604delAC	p.Thr535ArgfsTer3	frameshift	Exon 17 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Classic homocystinuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555869934; hg19: chr21-44474041;