rs148589243

Positions:

• chr21-43060514-C-A
• chr21-43060514-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000071.3(CBS):​c.1072G>T​(p.Val358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a helix (size 12) in uniprot entity CBS_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.29656482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1072G>T	p.Val358Leu	missense_variant	12/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1072G>T	p.Val358Leu	missense_variant	12/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239690 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 41134 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 21884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	16
DANN	Benign	0.64
DEOGEN2	Uncertain	0.66	D;D;D;D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	.;.;.;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.97	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.93	T;T;T;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.37
MutPred		0.49		Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);
MVP		0.58
MPC		0.35
ClinPred		0.087	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs148589243; hg19: chr21-44480624;