NM_000071.3:c.1616T>C

Variant names:

• chr21-43053920-A-G
• rs121964968
• NM_000071.3:c.1616T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.1616T>C​(p.Leu539Ser) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L539L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 8.67
• Publications: 12 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 13 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, 0.979
• PP5: Variant 21-43053920-A-G is Pathogenic according to our data. Variant chr21-43053920-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 124.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.1616T>C	p.Leu539Ser	missense	Exon 17 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1616T>C	p.Leu539Ser	missense	Exon 17 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1616T>C	p.Leu539Ser	missense	Exon 17 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.1616T>C	p.Leu539Ser	missense	Exon 17 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1616T>C	p.Leu539Ser	missense	Exon 17 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1616T>C	p.Leu539Ser	missense	Exon 17 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000668 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Classic homocystinuria (1)
1	-	-	Homocystinuria (1)
1	-	-	Homocystinuria, pyridoxine-responsive (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		8.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.98
Mutation Taster		=2/98	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: rs121964968; hg19: chr21-44474030;