chr21-43065278-TAGAAAGAG-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. 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 (★★).

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 21-43065278-TAGAAAGAG-T is Pathogenic according to our data. Variant chr21-43065278-TAGAAAGAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.667-14_667-7delCTCTTTCT		splice_region_variant, intron_variant	Intron 7 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.667-14_667-7delCTCTTTCT		splice_region_variant, intron_variant	Intron 7 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135876

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:3

Aug 01, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Oct 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667-14_667-7delCTCTTTCT intronic variant, located in intron 5 of the CBS gene, results from a deletion of 8 nucleotides within intron 5 of the CBS gene. This variant has been identified in conjunction with other CBS variant(s) in individual(s) with features consistent with homocystinuria, and in at least one instance, the variants were identified in trans (Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Lorenzini M et al. J Inherit Metab Dis, 2018 Jan;41:109-115; Asamoah A et al. Int J Neonatal Screen, 2021 Jul;7:[ePub ahead of print]). In a minigene assay, this variant showed complete aberrant splicing that resulted in exon skipping with an out-of-frame transcript (Cozar M et al. Hum Mutat, 2011 Jul;32:835-42). This nucleotide positions are not well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the CBS gene. It does not directly change the encoded amino acid sequence of the CBS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs764160782, gnomAD 0.002%). This variant has been observed in individual(s) with homocystinuria (PMID: 21520339, 28980096; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188911). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21520339). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 23, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional analysis found that c.667-14_667-7delCTCTTTCT results in exon 6 skipping and produces a frameshift (Cozar et al., 2011).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21520339) -

Homocystinuria Pathogenic:1

Nov 26, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.667-14_667-7delCTCTTTCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 3 prime acceptor site, while two predict the variant weakens a 3 prime acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating exon 6 skipping in a minigene assay that would produce a frameshift (Cozar 2011). This variant was named using the reference sequence NG_008938.1; cDNA, ENST00000352178 in this report. The variant allele was found at a frequency of 7.2e-06 in 277014 control chromosomes (gnomAD). c.667-14_667-7delCTCTTTCT has been reported in the literature in two compound heterozygous siblings, who were affected with severe Homocystinuria (Cozar 2011). The variant has been also reported in other patients who also carried pathogenic CBS variants (Lorenzini 2018, Asamoah_2021). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs764160782; hg19: chr21-44485388;