chr21-43056870-C-T

Variant names:

• chr21-43056870-C-T
• rs369903148
• NM_000071.3:c.1485G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6_Very_Strong BP7

The NM_000071.3(CBS):​c.1485G>A​(p.Thr495Thr) 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.979
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.205).
• BP6: Variant 21-43056870-C-T is Benign according to our data. Variant chr21-43056870-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 471360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.979 with no splicing effect.

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.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1485G>A	p.Thr495Thr	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.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000498 AC: 8 AN: 160758 AF XY: 0.0000590

Gnomad AFR exome AF: 0.000219

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.0000471

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000306 AC: 5 AN: 163136 Hom.: 0 Cov.: 0 AF XY: 0.0000339 AC XY: 3 AN XY: 88442

African (AFR) AF: 0.000210 AC: 1 AN: 4762

American (AMR) AF: 0.00 AC: 0 AN: 12794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3750

East Asian (EAS) AF: 0.00 AC: 0 AN: 10678

South Asian (SAS) AF: 0.00 AC: 0 AN: 32474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 658

European-Non Finnish (NFE) AF: 0.0000483 AC: 4 AN: 82900

Other (OTH) AF: 0.00 AC: 0 AN: 8178

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	0.093
DANN	Benign	0.66
PhyloP100		-0.98
Mutation Taster		=100/0	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: rs369903148; hg19: chr21-44476980; COSMIC: COSV61443357; COSMIC: COSV61443357;