21-43060528-G-A

Variant names:

• chr21-43060528-G-A
• rs121964972
• NM_000071.3:c.1058C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000071.3(CBS):​c.1058C>T​(p.Thr353Met) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249706: Functional studies have demonstrated that this variant results in reduced enzymatic activity (Mayfield et al., 2012)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T353T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.58
• Publications: 26 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249706: Functional studies have demonstrated that this variant results in reduced enzymatic activity (Mayfield et al., 2012);; SCV004033913: PS3:Supporting; SCV000769936: Experimental studies have shown that this missense change affects CBS function (PMID: 9156316, 14635102, 22267502).; SCV002555838: The variants' impact on protein function was evaluated in several different publications using recombinant protein recovered from E. coli cultures (Dawson_1997), yeast (Kruger_2003) and human cell lines (Lee_2005).; SCV000319360: In vitro functional studies of this alteration showed a substantial reduction in CBS activity and low growth in yeast assays (Kruger, 2003; Mayfield, 2012). In vitro expression studies of this alteration also demonstrated reduced enzyme activity in COS7 and NIH3T3 cells (Lee, 2005).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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, 0.936
• PP5: Variant 21-43060528-G-A is Pathogenic according to our data. Variant chr21-43060528-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 131.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.1058C>T	p.Thr353Met	missense	Exon 12 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1058C>T	p.Thr353Met	missense	Exon 12 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1058C>T	p.Thr353Met	missense	Exon 12 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.1058C>T	p.Thr353Met	missense	Exon 12 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1058C>T	p.Thr353Met	missense	Exon 12 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1058C>T	p.Thr353Met	missense	Exon 12 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000295 AC: 7 AN: 237672 AF XY: 0.0000383

Gnomad AFR exome AF: 0.000392

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000633 AC: 3 AN: 47412 Hom.: 0 Cov.: 0 AF XY: 0.0000791 AC XY: 2 AN XY: 25288

African (AFR) AF: 0.000701 AC: 2 AN: 2854

American (AMR) AF: 0.000248 AC: 1 AN: 4036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1052

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 7550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24414

Other (OTH) AF: 0.00 AC: 0 AN: 2414

GnomAD4 genome Cov.: 0

Alfa AF: 0.000205 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Classic homocystinuria (3)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	Homocystinuria, pyridoxine-nonresponsive (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.88	L
PhyloP100		4.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.059	B
Vest4		0.47
MVP		0.85
MPC		0.70
ClinPred		0.14	T
GERP RS		3.2
PromoterAI		0.095	Neutral
Varity_R		0.44
gMVP		0.82
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: rs121964972; hg19: chr21-44480638;