NM_000071.3:c.667-14_667-7delCTCTTTCT

Variant names:

• chr21-43065278-TAGAAAGAG-T
• rs764160782
• NM_000071.3:c.667-14_667-7delCTCTTTCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NM_000071.3(CBS):​c.667-14_667-7delCTCTTTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329209: Functional analysis found that c.667-14_667-7delCTCTTTCT results in exon 6 skipping and produces a frameshift (Cozar et al., 2011)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.77
• 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329209: Functional analysis found that c.667-14_667-7delCTCTTTCT results in exon 6 skipping and produces a frameshift (Cozar et al., 2011).; SCV000917109: This variant was found to affect mRNA splicing, demonstrating exon 6 skipping in a minigene assay that would produce a frameshift (Cozar 2011).; SCV000769931: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21520339).; SCV005545929: "In a minigene assay, this variant showed complete aberrant splicing that resulted in exon skipping with an out-of-frame transcript." PMID:21698884
• PP5: Variant 21-43065278-TAGAAAGAG-T is Pathogenic according to our data. Variant chr21-43065278-TAGAAAGAG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188911.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.667-14_667-7delCTCTTTCT		splice_region intron	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.667-14_667-7delCTCTTTCT		splice_region intron	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.667-14_667-7delCTCTTTCT		splice_region intron	N/A	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.667-14_667-7delCTCTTTCT		splice_region intron	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.667-14_667-7delCTCTTTCT		splice_region intron	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.667-14_667-7delCTCTTTCT		splice_region intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251350 AF XY: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1238636 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 619556

African (AFR) AF: 0.00 AC: 0 AN: 30878

American (AMR) AF: 0.00 AC: 0 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 79020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4984

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 917624

Other (OTH) AF: 0.00 AC: 0 AN: 52714

GnomAD4 genome Cov.: 15

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs764160782; hg19: chr21-44485388;