Variant chr21-43066310-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM1PP3_StrongPP5

The NM_000071.3(CBS):c.384G>C(p.Glu128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. E128E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 12)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.389

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

Transcript NM_000071.3 (CBS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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 NM_000071.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 21-43066310-C-G is Pathogenic according to our data. Variant chr21-43066310-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.384G>C	p.Glu128Asp	missense_variant	5/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.384G>C	p.Glu128Asp	missense_variant	5/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251054

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000666

AC:

AN:

900284

Hom.:

Cov.:

AF XY:

0.00000863

AC XY:

AN XY:

463522

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000787

Gnomad4 OTH exome

AF:

0.0000246

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Pathogenic

0.98

.;.;.;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.2

M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.011

D;D;D;D;D

Sift4G

Uncertain

0.057

T;T;T;T;D

Polyphen

0.29

B;B;B;B;.

Vest4

0.94

MutPred

0.80

Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);Loss of disorder (P = 0.2064);

MVP

0.72

MPC

0.37

ClinPred

0.87

GERP RS

2.4

Varity_R

0.54

gMVP

0.85

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over