rs376011228

chr21-43065278-TAGAA-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000071.3(CBS):c.667-10_667-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,359,468 control chromosomes in the GnomAD database, including 28 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (13 hom., cov: 15)
  • Exomes 𝑓: 0.000082 (15 hom.)
• Consequence: CBS NM_000071.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.238

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 21-43065278-TAGAA-T is Benign according to our data. Variant chr21-43065278-TAGAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000919 (111/120832) while in subpopulation AFR AF= 0.0032 (107/33474). AF 95% confidence interval is 0.00271. There are 13 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.667-10_667-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.667-10_667-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000071.3	P1

Frequencies

GnomAD3 genomes AF: 0.000870 AC: 105 AN: 120704 Hom.: 13 Cov.: 15

Gnomad AFR AF: 0.00303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000247

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000627

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251350 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135876

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000579

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: 0.000163

GnomAD4 exome AF: 0.0000815 AC: 101 AN: 1238636 Hom.: 15 AF XY: 0.0000726 AC XY: 45 AN XY: 619556

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.000141

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: 0.0000109

Gnomad4 OTH exome AF: 0.000209

GnomAD4 genome AF: 0.000919 AC: 111 AN: 120832 Hom.: 13 Cov.: 15 AF XY: 0.000991 AC XY: 58 AN XY: 58550

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.000246

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000618

Alfa AF: 0.000427 Hom.: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 13, 2020

The CBS c.667-10_667-7delTTCT variant (rs1060500684), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 405377). This variant is found in the African population with an overall allele frequency of 0.20% (50/24926 alleles) in the Genome Aggregation Database. This is an intronic variant that deletes four weakly-to-moderately conserved nucleotides, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. However, RNA studies would be required to confirm an effect on splicing. Given the lack of clinical and functional data, the significance of the c.667-10_667-7delTTCT variant is uncertain at this time. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Classic homocystinuria Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 29, 2020

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs376011228; hg19: chr21-44485388;