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. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000071.3(CBS):​c.1067T>G​(p.Val356Gly) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V356A) has been classified as Uncertain significance.

• 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
• Publications: 3 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3
• 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.

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.1067T>G	p.Val356Gly	missense	Exon 12 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1067T>G	p.Val356Gly	missense	Exon 12 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1067T>G	p.Val356Gly	missense	Exon 12 of 18	NP_001171480.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1067T>G	p.Val356Gly	missense	Exon 12 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1067T>G	p.Val356Gly	missense	Exon 12 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1067T>G	p.Val356Gly	missense	Exon 12 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00 AC: 0 AN: 238714 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 2730

American (AMR) AF: 0.00 AC: 0 AN: 3850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 930

East Asian (EAS) AF: 0.00 AC: 0 AN: 3176

South Asian (SAS) AF: 0.00 AC: 0 AN: 6770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22198

Other (OTH) AF: 0.00 AC: 0 AN: 2160

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.57	N
PhyloP100		1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.43
MutPred		0.71		Loss of stability (P = 0.0134)
MVP		0.41
MPC		0.46
ClinPred		0.17	T
GERP RS		-0.12
PromoterAI		-0.039	Neutral
Varity_R		0.33
gMVP		0.85
Mutation Taster		=63/37	polymorphism

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: rs370163789; hg19: chr21-44480629;