rs370163789

Variant names:

• chr21-43060519-A-C
• rs370163789
• NM_000071.3:c.1067T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-43060519-A-C
• chr21-43060519-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000071.3(CBS):​c.1067T>G​(p.Val356Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 1.24

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 2 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1067T>G	p.Val356Gly	missense_variant	Exon 12 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1067T>G	p.Val356Gly	missense_variant	Exon 12 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 43102 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22962

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	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	11
DANN	Benign	0.53
DEOGEN2	Pathogenic	0.90	D;D;D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.73	.;.;.;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.57	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.43
MutPred		0.71		Loss of stability (P = 0.0134);Loss of stability (P = 0.0134);Loss of stability (P = 0.0134);Loss of stability (P = 0.0134);
MVP		0.41
MPC		0.46
ClinPred		0.17	T
GERP RS		-0.12
Varity_R		0.33
gMVP		0.85

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: rs370163789; hg19: chr21-44480629;