chr21-43056830-C-T

Variant names:

• chr21-43056830-C-T
• rs1060500680
• NM_000071.3:c.1525G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_000071.3(CBS):​c.1525G>A​(p.Ala509Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A509V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.49
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• 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, 0.922

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.1525G>A	p.Ala509Thr	missense	Exon 16 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1525G>A	p.Ala509Thr	missense	Exon 16 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1525G>A	p.Ala509Thr	missense	Exon 16 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.1525G>A	p.Ala509Thr	missense	Exon 16 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1525G>A	p.Ala509Thr	missense	Exon 16 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1525G>A	p.Ala509Thr	missense	Exon 16 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157880 AF XY: 0.00

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: 0.0000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000616 AC: 1 AN: 162220 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87944

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4774

American (AMR) AF: 0.00 AC: 0 AN: 12056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3740

East Asian (EAS) AF: 0.00 AC: 0 AN: 10332

South Asian (SAS) AF: 0.00 AC: 0 AN: 32504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 648

European-Non Finnish (NFE) AF: 0.0000120 AC: 1 AN: 83142

Other (OTH) AF: 0.00 AC: 0 AN: 8164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000355 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.5
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.92
MPC		0.59
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.78
gMVP		0.89
Mutation Taster		=22/78	disease causing

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: rs1060500680; hg19: chr21-44476940; COSMIC: COSV61441655; COSMIC: COSV61441655;