21-43053943-G-T

Variant names:

• chr21-43053943-G-T
• rs768230991
• NM_000071.3:c.1593C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000071.3(CBS):​c.1593C>A​(p.Phe531Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1593C>A	p.Phe531Leu	missense_variant	Exon 17 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1593C>A	p.Phe531Leu	missense_variant	Exon 17 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Uncertain	0.72	D;D;D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.94	.;.;.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.3	L;L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.013	B;B;B;B
Vest4		0.39
MutPred		0.46		Loss of catalytic residue at F531 (P = 0.1505);Loss of catalytic residue at F531 (P = 0.1505);Loss of catalytic residue at F531 (P = 0.1505);Loss of catalytic residue at F531 (P = 0.1505);
MVP		0.30
MPC		0.41
ClinPred		0.35	T
GERP RS		-4.2
Varity_R		0.52
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768230991; hg19: chr21-44474053;