chr21-43068529-A-G

Variant names:

• chr21-43068529-A-G
• rs112029370
• NM_000071.3:c.296T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000071.3(CBS):​c.296T>C​(p.Phe99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F99Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 6)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.670
• Publications: 0 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 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19022945).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.296T>C	p.Phe99Ser	missense	Exon 4 of 17	NP_000062.1
	CBS	NM_001178008.3		c.296T>C	p.Phe99Ser	missense	Exon 4 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.296T>C	p.Phe99Ser	missense	Exon 4 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.296T>C	p.Phe99Ser	missense	Exon 4 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.296T>C	p.Phe99Ser	missense	Exon 4 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.296T>C	p.Phe99Ser	missense	Exon 4 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.0000257 AC: 1 AN: 38986 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000548

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000293 AC: 1 AN: 340968 Hom.: 0 Cov.: 0 AF XY: 0.00000545 AC XY: 1 AN XY: 183546

African (AFR) AF: 0.00 AC: 0 AN: 8940

American (AMR) AF: 0.00 AC: 0 AN: 22662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11414

East Asian (EAS) AF: 0.00 AC: 0 AN: 26726

South Asian (SAS) AF: 0.00 AC: 0 AN: 43508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1440

European-Non Finnish (NFE) AF: 0.00000535 AC: 1 AN: 186800

Other (OTH) AF: 0.00 AC: 0 AN: 18880

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000512 AC: 2 AN: 39074 Hom.: 0 Cov.: 6 AF XY: 0.0000556 AC XY: 1 AN XY: 17998

African (AFR) AF: 0.000122 AC: 1 AN: 8198

American (AMR) AF: 0.00 AC: 0 AN: 5300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1144

East Asian (EAS) AF: 0.00 AC: 0 AN: 1766

South Asian (SAS) AF: 0.00 AC: 0 AN: 990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0000548 AC: 1 AN: 18260

Other (OTH) AF: 0.00 AC: 0 AN: 512

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.36	N
PhyloP100		0.67
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.087	B
Vest4		0.53
MutPred		0.53		Gain of disorder (P = 0.0092)
MVP		0.46
MPC		0.65
ClinPred		0.48	T
GERP RS		-3.7
Varity_R		0.22
gMVP		0.86
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs112029370; hg19: chr21-44488639;