21-43072061-G-A

Position:

• chr21-43072061-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000071.3(CBS):​c.133C>T​(p.Arg45Trp) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.95

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013109982).
• BP6: Variant 21-43072061-G-A is Benign according to our data. Variant chr21-43072061-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.133C>T	p.Arg45Trp	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.133C>T	p.Arg45Trp	missense_variant	3/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000658 AC: 165 AN: 250626 Hom.: 1 AF XY: 0.000789 AC XY: 107 AN XY: 135662

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00180

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000395 Hom.: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 12, 2024

Variant summary: CBS c.133C>T (p.Arg45Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 250626 control chromosomes, including one homozygote, and predominantly at a frequency of 0.0041 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003). To our knowledge, no occurrence of c.133C>T in individuals affected with Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 212871). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Classic homocystinuria Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 29, 2019

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.64
MVP		0.90
MPC		0.74
ClinPred		0.078	T
GERP RS		3.6
Varity_R		0.24
gMVP		0.79

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: rs201372812; hg19: chr21-44492171; COSMIC: COSV61445942; COSMIC: COSV61445942;