21-43056876-C-T

Variant names:

• chr21-43056876-C-T
• rs143225442
• NM_000071.3:c.1479G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_000071.3(CBS):​c.1479G>A​(p.Thr493Thr) variant causes a synonymous 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T493T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00035 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -2.33
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP6: Variant 21-43056876-C-T is Benign according to our data. Variant chr21-43056876-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212834.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1479G>A	p.Thr493Thr	synonymous	Exon 16 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1479G>A	p.Thr493Thr	synonymous	Exon 16 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1479G>A	p.Thr493Thr	synonymous	Exon 16 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.1479G>A	p.Thr493Thr	synonymous	Exon 16 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1479G>A	p.Thr493Thr	synonymous	Exon 16 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1479G>A	p.Thr493Thr	synonymous	Exon 16 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 2474 Hom.: 0 Cov.: 0

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000368 AC: 59 AN: 160528 AF XY: 0.000331

Gnomad AFR exome AF: 0.000220

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000858

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000676

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000346 AC: 56 AN: 162074 Hom.: 2 Cov.: 0 AF XY: 0.000319 AC XY: 28 AN XY: 87886

African (AFR) AF: 0.000422 AC: 2 AN: 4734

American (AMR) AF: 0.000157 AC: 2 AN: 12772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3714

East Asian (EAS) AF: 0.00 AC: 0 AN: 10710

South Asian (SAS) AF: 0.000155 AC: 5 AN: 32332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6944

Middle Eastern (MID) AF: 0.00157 AC: 1 AN: 638

European-Non Finnish (NFE) AF: 0.000524 AC: 43 AN: 82044

Other (OTH) AF: 0.000366 AC: 3 AN: 8186

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2482 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1250

African (AFR) AF: 0.00 AC: 0 AN: 94

American (AMR) AF: 0.00 AC: 0 AN: 1090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 58

East Asian (EAS) AF: 0.00 AC: 0 AN: 184

South Asian (SAS) AF: 0.00 AC: 0 AN: 150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 98

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 20

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 734

Other (OTH) AF: 0.00 AC: 0 AN: 42

Alfa AF: 0.000238 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	Classic homocystinuria (2)
-	1	1	not specified (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.076
DANN	Benign	0.65
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

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: rs143225442; hg19: chr21-44476986; COSMIC: COSV61445315; COSMIC: COSV61445315;