rs794727835

Variant names:

• chr21-43065499-CCCAGTGCCCGCAGCACGT-C
• rs794727835
• NM_000071.3:c.536_553delACGTGCTGCGGGCACTGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_000071.3(CBS):​c.536_553delACGTGCTGCGGGCACTGG​(p.Asp179_Leu184del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 410,816 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D179D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CBS NM_000071.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 7.79
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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
• PP5: Variant 21-43065499-CCCAGTGCCCGCAGCACGT-C is Pathogenic according to our data. Variant chr21-43065499-CCCAGTGCCCGCAGCACGT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198388.

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.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 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.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248946 AF XY: 0.0000148

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: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 2 AN: 410816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 217014

African (AFR) AF: 0.00 AC: 0 AN: 12904

American (AMR) AF: 0.00 AC: 0 AN: 27198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12876

East Asian (EAS) AF: 0.00 AC: 0 AN: 31152

South Asian (SAS) AF: 0.00 AC: 0 AN: 47628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1768

European-Non Finnish (NFE) AF: 0.00000878 AC: 2 AN: 227916

Other (OTH) AF: 0.00 AC: 0 AN: 23504

GnomAD4 genome Cov.: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Classic homocystinuria (3)
1	1	-	not provided (2)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs794727835; hg19: chr21-44485609;