21-43058862-C-T

Variant names:

• chr21-43058862-C-T
• rs28934891
• NM_000071.3:c.1330G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP2 PP5_Very_Strong

The NM_000071.3(CBS):​c.1330G>A​(p.Asp444Asn) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000543508: Experimental studies have shown that this missense change affects CBS function (PMID:8755636, 14722619, 20490928, 20506325, 22069143, 25044645)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D444D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.50
• Publications: 41 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000543508: Experimental studies have shown that this missense change affects CBS function (PMID: 8755636, 14722619, 20490928, 20506325, 22069143, 25044645).; SCV000249732: Published functional studies demonstrate a damaging effect as this variant disrupts CBS protein interaction with S-adenosylmethionine (also called SAM or AdoMet), a cofactor needed for CBS allosteric activation and protein stability, thus causing reduced CBS protein levels and impairing its ability to be properly activated by physiological levels of SAM (Kluijtmans et al., 1996; Evande et al., 2002; Scott et al., 2004; Prudova et al., 2006; Mendes et al., 2014a; Mendes et al., 2014b; Alcaide et al., 2015); SCV000803554: Well-established functional studies show a deleterious effect (PMID:12269827,23974653,20506325,8755636).; SCV000914970: Functional studies were performed using cultured fibroblasts from a patient and showed that the p.Asp444Asn variant was not stimulated by physiological levels of S-Adenosylmethionine (AdoMet; a protein which stimulates CBS activity) compared to control fibroblasts, and required increased levels for stimulation (Kluijtmans et al. 1996; Evande et al. 2002).; SCV000919081: Functional studies suggest that CBS expression and activity levels are similar to those found in heterozygous individuals, but binding with the necessary cofactor S-adenosylmethionine and the subsequent induction of CBS protein activity is impaired (Mendes_2013).; SCV002692917: Although exhibiting high level of enzyme activity in in vitro assays (Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Mendes MI et al. Hum. Mutat., 2014 Oct;35:1195-202), this alteration has been reported to render the mutant protein unresponsive to the allosteric regulator S-adenosylmethionine, which could subsequently affect protein stability and function (Kluijtmans LA et al. J. Clin. Invest., 1996 Jul;98:285-9; Evande R et al. Biochemistry, 2002 Oct;41:11832-7; Scott JW et al. J. Clin. Invest., 2004 Jan;113:274-84; Mendes MI et al. Hum. Mutat., 2014 Oct;35:1195-202).
• 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.
• PP5: Variant 21-43058862-C-T is Pathogenic according to our data. Variant chr21-43058862-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126.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.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1330G>A	p.Asp444Asn	missense	Exon 14 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.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000334 AC: 56 AN: 167900 AF XY: 0.000314

Gnomad AFR exome AF: 0.000206

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.000649

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000360 Hom.: 0

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000153 AC: 18

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Classic homocystinuria (7)
3	-	-	not provided (3)
2	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (2)
1	-	-	CBS-related disorder (1)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	Homocystinuria, pyridoxine-responsive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.60
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.12	B
Vest4		0.93
MVP		0.90
MPC		0.42
ClinPred		0.14	T
GERP RS		4.7
PromoterAI		0.0090	Neutral
Varity_R		0.75
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28934891; hg19: chr21-44478972;