chr21-43053893-C-T

Position:

• chr21-43053893-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000071.3(CBS):​c.1643G>A​(p.Arg548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.808

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004730016).
• BP6: Variant 21-43053893-C-T is Benign according to our data. Variant chr21-43053893-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43053893-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1643G>A	p.Arg548Gln	missense_variant	17/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1643G>A	p.Arg548Gln	missense_variant	17/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00157 AC: 391 AN: 249094 Hom.: 1 AF XY: 0.00183 AC XY: 247 AN XY: 135074

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.000929

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00149

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00213 Hom.: 0

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00166 AC: 201

EpiCase AF: 0.00213

EpiControl AF: 0.00297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 21, 2022	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 16429402) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CBS: PM5:Supporting, PS3:Supporting, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 22, 2024

Variant summary: CBS c.1643G>A (p.Arg548Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 249094 control chromosomes, including one homozygote, and predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the maximum frequency estimated for a pathogenic variant in CBS causing Homocystinuria (0.0025 vs 0.003), suggesting the variant could be a benign polymorphism found primarily in individuals of Non-Finnish European ancestry. c.1643G>A has been reported in the literature in the heterozygous state in an individual affected with Homocystinuria in whom no other CBS variants were identified (Urreizti_2006). This report does not provide unequivocal conclusions about association of the variant with Homocystinuria. A functional study found the variant retained approximately 60% of WT activity, responded to cofactor and allosteric activator similar to the WT enzyme, and was able to form tetramers in vitro (Urreizti_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16429402).ClinVar contains an entry for this variant (Variation ID: 212869). 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 20, 2018

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. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

CBS-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.36	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.77	.;.;.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	0.27	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.020	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0070	B;B;B;B
Vest4		0.051
MVP		0.41
MPC		0.40
ClinPred		0.0035	T
GERP RS		0.93
Varity_R		0.10
gMVP		0.49

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: rs150828989; hg19: chr21-44474003;