rs121964965

Positions:

chr21-43066279-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PP3_StrongPP5BS2_Supporting

The ENST00000398165.8(CBS):c.415G>A(p.Gly139Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000095 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000095 ( 2 hom. )

Consequence

CBS
ENST00000398165.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.84

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000398165.8

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 21-43066279-C-T is Pathogenic according to our data. Variant chr21-43066279-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 121.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr21-43066279-C-T is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.415G>A	p.Gly139Arg	missense_variant	5/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.415G>A	p.Gly139Arg	missense_variant	5/17	1	NM_000071.3	ENSP00000381231	P1	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00000947

AC:

AN:

105604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250444

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000949

AC:

AN:

1054038

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

534946

show subpopulations

Gnomad4 AFR exome

AF:

0.0000581

Gnomad4 AMR exome

AF:

0.0000473

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000782

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000517

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000947

AC:

AN:

105640

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

51278

show subpopulations

Gnomad4 AFR

AF:

0.0000527

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000974

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Homocystinuria, pyridoxine-responsive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1995

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 139 of the CBS protein (p.Gly139Arg). This variant is present in population databases (rs121964965, gnomAD 0.01%). This missense change has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 7611293). ClinVar contains an entry for this variant (Variation ID: 121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 06, 2022

Variant summary: CBS c.415G>A (p.Gly139Arg) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of 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 2.8e-05 in 250444 control chromosomes (gnomAD). c.415G>A has been reported in the literature in at least one compound heterozygous individual affected with Homocystinuria (Shih_1995). These data do not allow any conclusion about variant significance. One publication using a yeast ortholog replacement assay reports experimental evidence indicating the variant has an intermediate phenotype that is responsive to B6 supplementation (Mayfield_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

.;.;.;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;H;H;H;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-8.0

D;D;D;D;D

REVEL

Pathogenic

0.93

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

0.94

MutPred

0.86

Gain of phosphorylation at T141 (P = 0.0948);Gain of phosphorylation at T141 (P = 0.0948);Gain of phosphorylation at T141 (P = 0.0948);Gain of phosphorylation at T141 (P = 0.0948);Gain of phosphorylation at T141 (P = 0.0948);

MVP

0.94

MPC

1.2

ClinPred

1.0

GERP RS

5.2

Varity_R

0.90

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over