chr21-43065678-C-T

Variant names:

• chr21-43065678-C-T
• rs199817801
• NM_000071.3:c.469G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP6

The NM_000071.3(CBS):​c.469G>A​(p.Ala157Thr) variant causes a missense change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.07
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3
• 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.
• BP6: Variant 21-43065678-C-T is Benign according to our data. Variant chr21-43065678-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263924.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.469G>A	p.Ala157Thr	missense	Exon 6 of 17	NP_000062.1
	CBS	NM_001178008.3		c.469G>A	p.Ala157Thr	missense	Exon 6 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.469G>A	p.Ala157Thr	missense	Exon 6 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.469G>A	p.Ala157Thr	missense	Exon 6 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.469G>A	p.Ala157Thr	missense	Exon 6 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.469G>A	p.Ala157Thr	missense	Exon 6 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 1 AN: 1072 Hom.: 0 Cov.: 0

Gnomad AFR 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: 0.00275

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 169444 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000113 AC: 3 AN: 265004 Hom.: 0 Cov.: 0 AF XY: 0.0000143 AC XY: 2 AN XY: 140094

African (AFR) AF: 0.000124 AC: 1 AN: 8078

American (AMR) AF: 0.00 AC: 0 AN: 13438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7350

East Asian (EAS) AF: 0.00 AC: 0 AN: 21520

South Asian (SAS) AF: 0.00 AC: 0 AN: 39400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1064

European-Non Finnish (NFE) AF: 0.0000138 AC: 2 AN: 144768

Other (OTH) AF: 0.00 AC: 0 AN: 14706

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000935 AC: 1 AN: 1070 Hom.: 0 Cov.: 0 AF XY: 0.00182 AC XY: 1 AN XY: 548

African (AFR) AF: 0.00 AC: 0 AN: 150

American (AMR) AF: 0.00 AC: 0 AN: 216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18

East Asian (EAS) AF: 0.00 AC: 0 AN: 180

South Asian (SAS) AF: 0.00 AC: 0 AN: 108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00278 AC: 1 AN: 360

Other (OTH) AF: 0.00 AC: 0 AN: 18

Alfa AF: 0.0000936 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Classic homocystinuria (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.11	B
Vest4		0.49
MVP		0.61
MPC		0.43
ClinPred		0.62	D
GERP RS		2.9
Varity_R		0.16
gMVP		0.83
Mutation Taster		=23/77	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: rs199817801; hg19: chr21-44485788;