NM_000071.3:c.393G>C

Variant names:

• chr21-43066301-C-G
• rs1555875351
• NM_000071.3:c.393G>C
• CBS p.Glu131Asp

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Strong

The NM_000071.3(CBS):​c.393G>C​(p.Glu131Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.0000064 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.84
• 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: ClinGen, Genomics England PanelApp, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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, 0.987

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.393G>C	p.Glu131Asp	missense	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.393G>C	p.Glu131Asp	missense	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.393G>C	p.Glu131Asp	missense	Exon 5 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.393G>C	p.Glu131Asp	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.393G>C	p.Glu131Asp	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.393G>C	p.Glu131Asp	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000644 AC: 6 AN: 931006 Hom.: 2 Cov.: 14 AF XY: 0.00000837 AC XY: 4 AN XY: 477820

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15616

American (AMR) AF: 0.00 AC: 0 AN: 41790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20348

East Asian (EAS) AF: 0.00 AC: 0 AN: 37724

South Asian (SAS) AF: 0.00 AC: 0 AN: 70636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3586

European-Non Finnish (NFE) AF: 0.00000905 AC: 6 AN: 662966

Other (OTH) AF: 0.00 AC: 0 AN: 41840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 14

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Classic homocystinuria (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		1.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Varity_R		0.92
gMVP		0.88
Mutation Taster		=2/98	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555875351;

hg19: chr21-44486411;