Genetic Variant NM_000071.3:c.415G>A (chr21-43066279-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM1PP2PP3_StrongPP5BS2_Supporting

The NM_000071.3(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
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.84

Publications

8 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000071.3

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, 0.983

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 VariationId is 121.

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.

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.415G>A	p.Gly139Arg	missense	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.415G>A	p.Gly139Arg	missense	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.415G>A	p.Gly139Arg	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.415G>A	p.Gly139Arg	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.415G>A	p.Gly139Arg	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.415G>A	p.Gly139Arg	missense	Exon 5 of 18	ENSP00000352643.3	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

GnomAD2 exomes

AF:

0.0000280

AC:

AN:

250444

AF XY:

0.0000369

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 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

African (AFR)

AF:

0.0000581

AC:

AN:

17210

American (AMR)

AF:

0.0000473

AC:

AN:

42314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21126

East Asian (EAS)

AF:

0.0000782

AC:

AN:

38376

South Asian (SAS)

AF:

0.00

AC:

AN:

73622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3986

European-Non Finnish (NFE)

AF:

0.00000517

AC:

AN:

773072

Other (OTH)

AF:

0.00

AC:

AN:

45802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000947

AC:

AN:

105640

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

51278

show subpopulations

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

African (AFR)

AF:

0.0000527

AC:

AN:

18962

American (AMR)

AF:

0.00

AC:

AN:

12058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2720

East Asian (EAS)

AF:

0.00

AC:

AN:

4628

South Asian (SAS)

AF:

0.00

AC:

AN:

3442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53048

Other (OTH)

AF:

0.00

AC:

AN:

1504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000906

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (1)

Homocystinuria, pyridoxine-responsive (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

PhyloP100

6.8

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.86

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

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

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