rs886057100

Variant names:

• chr21-43066321-G-A
• rs886057100
• NM_000071.3:c.373C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.373C>T​(p.Arg125Trp) 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 ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000436227: Functional studies in individual fibroblasts showed that the variant resulted in less than 2.5% of the CBS activity seen in unaffected individuals (Chwatko et al. 2007)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.962
• Publications: 3 publications found

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

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000436227: Functional studies in individual fibroblasts showed that the variant resulted in less than 2.5% of the CBS activity seen in unaffected individuals (Chwatko et al. 2007).; SCV001339043: Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated absent or less than 4% residual activities in patient derived fibroblasts (Kluijtmans_1999, Urreizti_2003) and in a bacterial expression system (Urreizti_2006).; SCV001580705: Experimental studies have shown that this missense change affects CBS function (PMID: 16429402).; SCV004563700: Functional analyses show the variant protein has decreased expression compared to wild type (Urreizti 2006), and CBS activity in patient derived fibroblasts was less than 2.5% compared to unaffected individuals (Chwatko 2007). PMID: 17327360; PMID: 16429402
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066320-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 197625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.985
• PP5: Variant 21-43066321-G-A is Pathogenic according to our data. Variant chr21-43066321-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 340089.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.373C>T	p.Arg125Trp	missense	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.373C>T	p.Arg125Trp	missense	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.373C>T	p.Arg125Trp	missense	Exon 5 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.373C>T	p.Arg125Trp	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.373C>T	p.Arg125Trp	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.373C>T	p.Arg125Trp	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251030 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000121 AC: 1 AN: 829620 Hom.: 0 Cov.: 12 AF XY: 0.00000233 AC XY: 1 AN XY: 429930

African (AFR) AF: 0.00 AC: 0 AN: 14648

American (AMR) AF: 0.0000244 AC: 1 AN: 41064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19614

East Asian (EAS) AF: 0.00 AC: 0 AN: 36974

South Asian (SAS) AF: 0.00 AC: 0 AN: 68520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 572316

Other (OTH) AF: 0.00 AC: 0 AN: 38352

GnomAD4 genome Cov.: 11

Alfa AF: 0.0000508 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Classic homocystinuria (4)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.96
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.92		Loss of disorder (P = 0.0126)
MVP		0.91
MPC		1.1
ClinPred		0.98	D
GERP RS		2.1
Varity_R		0.93
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886057100; hg19: chr21-44486431;