21-43072039-C-T

Position:

• chr21-43072039-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000071.3(CBS):​c.155G>A​(p.Cys52Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.54

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.155G>A	p.Cys52Tyr	missense_variant	3/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.155G>A	p.Cys52Tyr	missense_variant	3/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250454 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135582

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense variant c.155G>A(p.Cys52Tyr) in the CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain significance. However no details are available for independent assessment. A different amino acid change (p.C52R) affecting the same codon has been reported in compound heterozygous state in one individual with Hyperhomocysteinemia (An H, et al., 2018). The amino acid Cysteine at position 52 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. Additional studies are required to determine the pathogenicity of this variant. For these reasons, this variant has been classified as Uncertain Significance. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces cysteine with tyrosine at codon 52 of the CBS protein (p.Cys52Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs779777933, ExAC 0.006%). This missense change has been observed in individual(s) with cystathionine beta-synthase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 538697). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Cys52 amino acid residue in CBS. Other variant(s) that disrupt this residue have been observed in individuals with CBS-related conditions (PMID: 30246729; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;.;.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-9.8	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.92
MutPred		0.48		Gain of phosphorylation at C52 (P = 0.0422);Gain of phosphorylation at C52 (P = 0.0422);Gain of phosphorylation at C52 (P = 0.0422);Gain of phosphorylation at C52 (P = 0.0422);Gain of phosphorylation at C52 (P = 0.0422);
MVP		0.94
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs779777933; hg19: chr21-44492149;