rs147040567

chr21-43063051-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000071.3(CBS):c.856A>G(p.Ile286Val) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I286T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 4.09

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 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.25584212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.856A>G	p.Ile286Val	missense_variant	10/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.856A>G	p.Ile286Val	missense_variant	10/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000110 AC: 26 AN: 236066 Hom.: 0 AF XY: 0.000141 AC XY: 18 AN XY: 127924

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000175

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.000295 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Oct 06, 2017	This 6 year old male with global developmental delays is a compound heterozygote for 2 VUSs in the CBS gene (p.Glu283Lys and p.Ile286Val). The p.Ile286Val variant is present in the gnomAD non-Finnish European population at a frequency of 0.02%. Computational models predict it to benign. He has normal stature (30%tile). Subsequent clinical testing showed normal plasma homocysteine and methionine levels. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2018	The I286V variant of uncertain significance in the CBS gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 29/256,192 (0.01%) alleles globally, from individuals in large population cohorts (Lek et al., 2016). The I286V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The p.I286V variant (also known as c.856A>G), located in coding exon 8 of the CBS gene, results from an A to G substitution at nucleotide position 856. The isoleucine at codon 286 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the CBS protein (p.Ile286Val). This variant is present in population databases (rs147040567, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212855). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Benign	0.071
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Uncertain	0.76	D;D;D;D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Benign	0.21	N;N;N;N
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.015	B;B;B;B
Vest4		0.39
MVP		0.49
MPC		0.30
ClinPred		0.049	T
GERP RS		2.0
Varity_R		0.25
gMVP		0.71

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: rs147040567; hg19: chr21-44483161;