rs863223436

Variant names:

• chr21-43060516-GCCACCGCCA-G
• rs863223436
• NM_000071.3:c.1061_1069delTGGCGGTGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_000071.3(CBS):​c.1061_1069delTGGCGGTGG​(p.Val354_Val356del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.84
• 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: ClinGen, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000071.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000071.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 of 18	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1061_1069delTGGCGGTGG	p.Val354_Val356del	disruptive_inframe_deletion	Exon 12 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: Uncertain significance

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		8.8

Splicing

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

Other links and lift over

dbSNP: rs863223436; hg19: chr21-44480626;