rs1347662650

Variant names:

• chr21-43068541-A-G
• rs1347662650
• NM_000071.3:c.284T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-43068541-A-G
• chr21-43068541-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5

The NM_000071.3(CBS):​c.284T>C​(p.Ile95Thr) 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000649831: Experimental studies have shown that this missense change affects CBS function (PMID:29352562).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 6)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.92
• 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000649831: Experimental studies have shown that this missense change affects CBS function (PMID: 29352562).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43068541-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2908113.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, 0.98
• PP5: Variant 21-43068541-A-G is Pathogenic according to our data. Variant chr21-43068541-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471361.

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.284T>C	p.Ile95Thr	missense	Exon 4 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.284T>C	p.Ile95Thr	missense	Exon 4 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.284T>C	p.Ile95Thr	missense	Exon 4 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.284T>C	p.Ile95Thr	missense	Exon 4 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.284T>C	p.Ile95Thr	missense	Exon 4 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.284T>C	p.Ile95Thr	missense	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251396 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000112 AC: 4 AN: 355624 Hom.: 0 Cov.: 0 AF XY: 0.00000522 AC XY: 1 AN XY: 191474

African (AFR) AF: 0.00 AC: 0 AN: 9306

American (AMR) AF: 0.0000442 AC: 1 AN: 22606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11860

East Asian (EAS) AF: 0.0000365 AC: 1 AN: 27372

South Asian (SAS) AF: 0.00 AC: 0 AN: 45130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1524

European-Non Finnish (NFE) AF: 0.0000102 AC: 2 AN: 196744

Other (OTH) AF: 0.00 AC: 0 AN: 19646

GnomAD4 genome Cov.: 6

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Classic homocystinuria (3)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.83		Loss of stability (P = 0.0148)
MVP		0.89
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1347662650; hg19: chr21-44488651;