21-43065481-G-A

Variant names:

• chr21-43065481-G-A
• rs121964973
• NM_000071.3:c.572C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 19P and 1B. PS3 PM5 PP2 PP3_Strong PP5_Very_Strong BS2_Supporting

The NM_000071.3(CBS):​c.572C>T​(p.Thr191Met) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249685: Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T191K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 4)
  • Exomes 𝑓: 0.000062 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.36
• Publications: 40 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249685: Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., 2012; Hnzda A et al., 2012); SCV003841740: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:16429402, 22069143; SCV000695307: Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012).; SCV000769933: Experimental studies have shown that this missense change affects CBS function (PMID: 10338090, 16429402, 22069143, 22267502).; SCV004735389: Functional studies indicate that this amino acid change decreases the native folding of the encoded protein, substantially decreasing enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2011. PubMed ID: 22069143; Alcaide et al. 2014. PubMed ID: 25218699).; SCV003677654: Functional assays showed reduction in enzyme activity (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065481-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431934.
• 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, 0.991
• PP5: Variant 21-43065481-G-A is Pathogenic according to our data. Variant chr21-43065481-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.572C>T	p.Thr191Met	missense	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.572C>T	p.Thr191Met	missense	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.572C>T	p.Thr191Met	missense	Exon 7 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.572C>T	p.Thr191Met	missense	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.572C>T	p.Thr191Met	missense	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.572C>T	p.Thr191Met	missense	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 17072 Hom.: 0 Cov.: 4

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: 0.0000602 AC: 15 AN: 249042 AF XY: 0.0000519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

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: 0.000329

GnomAD4 exome AF: 0.0000624 AC: 26 AN: 416838 Hom.: 7 Cov.: 0 AF XY: 0.0000771 AC XY: 17 AN XY: 220480

African (AFR) AF: 0.00 AC: 0 AN: 13148

American (AMR) AF: 0.000746 AC: 21 AN: 28134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13228

East Asian (EAS) AF: 0.00 AC: 0 AN: 31198

South Asian (SAS) AF: 0.00 AC: 0 AN: 48444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1812

European-Non Finnish (NFE) AF: 0.0000217 AC: 5 AN: 230736

Other (OTH) AF: 0.00 AC: 0 AN: 23814

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 17072 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 7940

African (AFR) AF: 0.00 AC: 0 AN: 3974

American (AMR) AF: 0.00 AC: 0 AN: 1990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 414

East Asian (EAS) AF: 0.00 AC: 0 AN: 1014

South Asian (SAS) AF: 0.00 AC: 0 AN: 442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 7304

Other (OTH) AF: 0.00 AC: 0 AN: 230

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Classic homocystinuria (7)
2	-	-	not provided (2)
1	-	-	CBS-related disorder (1)
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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Loss of phosphorylation at T191 (P = 0.0306)
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.92
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121964973; hg19: chr21-44485591;