Genetic Variant NM_000071.3:c.442G>A (chr21-43066252-C-T) – ACMG Classification: Pathogenic (21 pts)

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.442G>A(p.Gly148Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001362174: The most pronounced variant effect results in <10% of normal activity (Kozich_2010, Katsushima_2005, Orendac_2004)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0000090 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.84

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

classic homocystinuria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

CBS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000071.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001362174: The most pronounced variant effect results in <10% of normal activity (Kozich_2010, Katsushima_2005, Orendac_2004).; SCV001229019: Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 16429402, 20490928, 20506325).; SCV002631193: This alteration has also been shown to have an impact on protein function (Meier M et al. Biochim Biophys Acta, 2003 Apr;1647:206-13; Orendáè M et al. Hum Mutat, 2004 Jun;23:631; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23).; SCV004014224: Published functional studies demonstrate a damaging effect: decreased enzyme activity and failure to restore function /rescue growth when expressed in a yeast system lacking the CBS ortholog (Kozich et al., 2010; Mayfield et al., 2012; Melenovska et al., 2015)

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066251-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1980875.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 21-43066252-C-T is Pathogenic according to our data. Variant chr21-43066252-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	NM_000071.3	MANE Select	c.442G>A	p.Gly148Arg	missense	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.442G>A	p.Gly148Arg	missense	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.442G>A	p.Gly148Arg	missense	Exon 5 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.442G>A	p.Gly148Arg	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.442G>A	p.Gly148Arg	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.442G>A	p.Gly148Arg	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00000879

AC:

AN:

113824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000776

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249522

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000898

AC:

AN:

1225432

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

613004

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000107

AC:

AN:

18662

American (AMR)

AF:

0.0000236

AC:

AN:

42356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21968

East Asian (EAS)

AF:

0.00

AC:

AN:

38844

South Asian (SAS)

AF:

0.00

AC:

AN:

76460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

0.00000859

AC:

AN:

931298

Other (OTH)

AF:

0.00

AC:

AN:

51258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000299538), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000879

AC:

AN:

113824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21274

American (AMR)

AF:

0.0000776

AC:

AN:

12890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2830

East Asian (EAS)

AF:

0.00

AC:

AN:

4832

South Asian (SAS)

AF:

0.00

AC:

AN:

3818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56570

Other (OTH)

AF:

0.00

AC:

AN:

1600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000216

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (3)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.8

PhyloP100

6.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over