rs772344567

Variant names:

• chr21-43056871-G-A
• rs772344567
• NM_000071.3:c.1484C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43056871-G-A
• chr21-43056871-G-T

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.1484C>T​(p.Thr495Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T495T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000074 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.53
• Publications: 1 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: ClinGen, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet

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, 0.881

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.1484C>T	p.Thr495Met	missense	Exon 16 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1484C>T	p.Thr495Met	missense	Exon 16 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1484C>T	p.Thr495Met	missense	Exon 16 of 18	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1484C>T	p.Thr495Met	missense	Exon 16 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1484C>T	p.Thr495Met	missense	Exon 16 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1484C>T	p.Thr495Met	missense	Exon 16 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 2360 Hom.: 0 Cov.: 0

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: 0.0000809 AC: 13 AN: 160610 AF XY: 0.0000236

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: 0.000157

Gnomad OTH exome AF: 0.000221

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000738 AC: 12 AN: 162594 Hom.: 0 Cov.: 0 AF XY: 0.0000567 AC XY: 5 AN XY: 88160

African (AFR) AF: 0.00 AC: 0 AN: 4778

American (AMR) AF: 0.00 AC: 0 AN: 12812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3750

East Asian (EAS) AF: 0.00 AC: 0 AN: 10698

South Asian (SAS) AF: 0.00 AC: 0 AN: 32316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 652

European-Non Finnish (NFE) AF: 0.000133 AC: 11 AN: 82510

Other (OTH) AF: 0.000122 AC: 1 AN: 8188

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2360 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1186

African (AFR) AF: 0.00 AC: 0 AN: 86

American (AMR) AF: 0.00 AC: 0 AN: 1030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 58

East Asian (EAS) AF: 0.00 AC: 0 AN: 164

South Asian (SAS) AF: 0.00 AC: 0 AN: 148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 88

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 708

Other (OTH) AF: 0.00 AC: 0 AN: 46

Alfa AF: 0.0000726 Hom.: 0

ExAC AF: 0.0000659 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Classic homocystinuria (3)
-	2	-	not provided (2)
-	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	0.099
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.45
Sift	Benign	0.051	T
Sift4G	Benign	0.099	T
Polyphen		0.96	D
Vest4		0.29
MVP		0.91
MPC		0.78
ClinPred		0.80	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.66
Mutation Taster		=81/19	polymorphism

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: rs772344567; hg19: chr21-44476981;