21-43066332-C-T

Variant names:

• chr21-43066332-C-T
• rs770095972
• NM_000071.3:c.362G>A

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.362G>A​(p.Arg121His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002060177: Functional assessments of this variant are available in the literature (PMID:16307898, 22267502)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 9)
  • Exomes 𝑓: 0.0000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.84
• Publications: 9 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: SCV002060177: Functional assessments of this variant are available in the literature (PMID: 16307898, 22267502).; SCV001361015: The most pronounced variant effect results in severely impaired enzyme activity resulting from impaired tetramer assembly (Katsushima_2006).; SCV001224398: Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 22267502).; SCV002615953: "In expression studies in E. coli, this variant showed decreased enzyme activity and impaired capability to correctly form tetramers (Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8). In a yeast growth assay, this variant was characterized as nonfunctional (Mayfield JA et al. Genetics, 2012 Apr;1309-1323)."
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066333-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2913713.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, 0.95
• PP5: Variant 21-43066332-C-T is Pathogenic according to our data. Variant chr21-43066332-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188948.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.362G>A	p.Arg121His	missense	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.362G>A	p.Arg121His	missense	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.362G>A	p.Arg121His	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.362G>A	p.Arg121His	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.362G>A	p.Arg121His	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.362G>A	p.Arg121His	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 74826 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00

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: 0.0000239 AC: 6 AN: 251070 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000885 AC: 7 AN: 791080 Hom.: 0 Cov.: 11 AF XY: 0.0000146 AC XY: 6 AN XY: 410534

African (AFR) AF: 0.0000699 AC: 1 AN: 14304

American (AMR) AF: 0.0000249 AC: 1 AN: 40238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19252

East Asian (EAS) AF: 0.00 AC: 0 AN: 36494

South Asian (SAS) AF: 0.00 AC: 0 AN: 67460

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2970

European-Non Finnish (NFE) AF: 0.00000556 AC: 3 AN: 539176

Other (OTH) AF: 0.0000270 AC: 1 AN: 36982

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 74826 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 35968

African (AFR) AF: 0.00 AC: 0 AN: 11194

American (AMR) AF: 0.00 AC: 0 AN: 8862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2026

East Asian (EAS) AF: 0.00 AC: 0 AN: 3676

South Asian (SAS) AF: 0.00 AC: 0 AN: 2280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39382

Other (OTH) AF: 0.00 AC: 0 AN: 998

Alfa AF: 0.0000617 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Classic homocystinuria (3)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.95
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.97
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: rs770095972; hg19: chr21-44486442; COSMIC: COSV61442706; COSMIC: COSV61442706;