rs778220779

Variant names:

• chr21-43066369-A-G
• rs778220779
• NM_000071.3:c.325T>C

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.325T>C​(p.Cys109Arg) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249727: "In a yeast system lacking the CBS ortholog, expression of a construct with C109R showed a failure to restore function/rescue growth (PMID:22267502, 12124992)"" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C109Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 7)
  • Exomes 𝑓: 0.000086 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.10
• Publications: 5 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: SCV000249727: "In a yeast system lacking the CBS ortholog, expression of a construct with C109R showed a failure to restore function/rescue growth (PMID: 22267502, 12124992)"; SCV005876998: in vitro functional analyses in a yeast ortholog demonstrate decreased CBS production and activity (Gaustadnes 2002, Mayfield 2012). PMID: 12124992. PMID: 22267502.; SCV004847626: "In vitro functional studies support an impact on protein function (Mayfield 2012)"; SCV000695304: Functional studies performed in yeast-based system showed conflicting results in experiments with B6 supplementation, low enzymatic activity and non-functional yeast phenotype.; SCV000649832: Experimental studies have shown that this missense change affects CBS function (PMID: 12124992, 22267502).; SCV005360414: "In vivo experimental studies suggest this variant impacts protein function (Gaustadnes et al. 2002. PubMed ID: 12124992; Mayfield et al. 2012. PubMed ID: 22267502)."
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066368-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2850167.Status of the report is criteria_provided_single_submitter, 1 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, 0.992
• PP5: Variant 21-43066369-A-G is Pathogenic according to our data. Variant chr21-43066369-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212878.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.325T>C	p.Cys109Arg	missense	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.325T>C	p.Cys109Arg	missense	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.325T>C	p.Cys109Arg	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.325T>C	p.Cys109Arg	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.325T>C	p.Cys109Arg	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.325T>C	p.Cys109Arg	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0000186 AC: 1 AN: 53796 Hom.: 0 Cov.: 7

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: 0.0000341

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250848 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

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: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000856 AC: 59 AN: 689364 Hom.: 3 Cov.: 9 AF XY: 0.0000778 AC XY: 28 AN XY: 359768

African (AFR) AF: 0.00 AC: 0 AN: 13158

American (AMR) AF: 0.00 AC: 0 AN: 37052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18092

East Asian (EAS) AF: 0.00 AC: 0 AN: 34654

South Asian (SAS) AF: 0.00 AC: 0 AN: 64276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2482

European-Non Finnish (NFE) AF: 0.000125 AC: 57 AN: 454206

Other (OTH) AF: 0.0000602 AC: 2 AN: 33232

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000186 AC: 1 AN: 53796 Hom.: 0 Cov.: 7 AF XY: 0.0000394 AC XY: 1 AN XY: 25350

African (AFR) AF: 0.00 AC: 0 AN: 6804

American (AMR) AF: 0.00 AC: 0 AN: 6596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1530

East Asian (EAS) AF: 0.00 AC: 0 AN: 2896

South Asian (SAS) AF: 0.00 AC: 0 AN: 1562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 114

European-Non Finnish (NFE) AF: 0.0000341 AC: 1 AN: 29338

Other (OTH) AF: 0.00 AC: 0 AN: 698

Alfa AF: 0.0000201 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Classic homocystinuria (5)
3	-	-	not provided (3)
1	-	-	CBS-related disorder (1)
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	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of MoRF binding (P = 0.026)
MVP		0.94
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		1.0
gMVP		0.99
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: rs778220779; hg19: chr21-44486479;