NM_000071.3:c.539T>C

Variant names:

• chr21-43065514-A-G
• rs1555875010
• NM_000071.3:c.539T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_000071.3(CBS):​c.539T>C​(p.Val180Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.0000075 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.79
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.539T>C	p.Val180Ala	missense	Exon 7 of 17	NP_000062.1
	CBS	NM_001178008.3		c.539T>C	p.Val180Ala	missense	Exon 7 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.539T>C	p.Val180Ala	missense	Exon 7 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.539T>C	p.Val180Ala	missense	Exon 7 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.539T>C	p.Val180Ala	missense	Exon 7 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.539T>C	p.Val180Ala	missense	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000746 AC: 3 AN: 401926 Hom.: 1 Cov.: 0 AF XY: 0.0000141 AC XY: 3 AN XY: 212144

African (AFR) AF: 0.00 AC: 0 AN: 12652

American (AMR) AF: 0.00 AC: 0 AN: 25934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12406

East Asian (EAS) AF: 0.00 AC: 0 AN: 31006

South Asian (SAS) AF: 0.00 AC: 0 AN: 46868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1732

European-Non Finnish (NFE) AF: 0.0000134 AC: 3 AN: 223214

Other (OTH) AF: 0.00 AC: 0 AN: 22990

GnomAD4 genome Cov.: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Classic homocystinuria Uncertain:1

Feb 20, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	-0.032
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.34	N
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.78
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.054	B
Vest4		0.69
MutPred		0.81		Gain of disorder (P = 0.0443)
MVP		0.79
MPC		0.74
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.76
gMVP		0.73
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1555875010; hg19: chr21-44485624;