Genetic Variant NM_000071.3:c.959T>C (chr21-43062391-A-G) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.959T>C(p.Val320Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V320V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.10

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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, 0.98

PP5

Variant 21-43062391-A-G is Pathogenic according to our data. Variant chr21-43062391-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 371028.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.959T>C	p.Val320Ala	missense	Exon 11 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.959T>C	p.Val320Ala	missense	Exon 11 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.959T>C	p.Val320Ala	missense	Exon 11 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.959T>C	p.Val320Ala	missense	Exon 11 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.959T>C	p.Val320Ala	missense	Exon 11 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.959T>C	p.Val320Ala	missense	Exon 11 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250352

AF XY:

0.0000148

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000272

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (2)

Homocystinuria (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.0

PhyloP100

8.1

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.91

Sift

Uncertain

0.028

Sift4G

Uncertain

0.024

Polyphen

0.98

Vest4

0.83

MutPred

0.86

Gain of disorder (P = 0.1046)

MVP

0.90

MPC

1.2

ClinPred

0.84

GERP RS

5.0

Varity_R

0.84

gMVP

0.94

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over