chr21-43053852-C-T

Position:

• chr21-43053852-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.*28G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.209

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.*28G>A		3_prime_UTR_variant	17/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.*28G>A		3_prime_UTR_variant	17/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000386 AC: 9 AN: 232876 Hom.: 0 AF XY: 0.0000634 AC XY: 8 AN XY: 126228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000288

Gnomad OTH exome AF: 0.000177

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2017

A variant of uncertain significance has been identified in the CBS gene. The c.*18+10 G>A variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server; Exome Aggregation Consortium). The c.*18+10 G>A variant occurs in the +10 position of a splice donor site for intron 17 in the alternate transcript noted above. This position is located downstream of the natural termination codon in all transcripts and is in the 3'UTR of the default transcript (NM_000071.2). In this alternate transcript, the sequence of intron 17 is predicted to be spliced out of the 3'UTR, whereas all other transcripts retain that sequence. This nucleotide substitution occurs at a position that is not conserved across species, and adenine (A) is wild type in several species. Several in silico splice prediction programs do not recognize this splice donor site in the alternate transcript and, in the absence of functional mRNA studies, the physiological consequences of this variant cannot be precisely determined. In addition, if normal splicing is disrupted, the biological and clinical consequence of aberrant splicing in this alternate transcript of CBS is unknown, as no other variants exclusive to this transcript have been reported to our knowledge. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.26
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs367597108; hg19: chr21-44473962;