rs61735859

Variant names:

• chr21-43060527-C-T
• rs61735859
• NM_000071.3:c.1059G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6 BP7

The NM_000071.3(CBS):​c.1059G>A​(p.Thr353Thr) 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).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00031 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.808
• Publications: 4 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.193).
• BP6: Variant 21-43060527-C-T is Benign according to our data. Variant chr21-43060527-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212827.
• BP7: Synonymous conserved (PhyloP=0.808 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.1059G>A	p.Thr353Thr	synonymous	Exon 12 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1059G>A	p.Thr353Thr	synonymous	Exon 12 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1059G>A	p.Thr353Thr	synonymous	Exon 12 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.1059G>A	p.Thr353Thr	synonymous	Exon 12 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1059G>A	p.Thr353Thr	synonymous	Exon 12 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1059G>A	p.Thr353Thr	synonymous	Exon 12 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad SAS AF: 0.00

GnomAD2 exomes AF: 0.000618 AC: 147 AN: 237886 AF XY: 0.000421

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000312 AC: 14 AN: 44908 Hom.: 1 Cov.: 0 AF XY: 0.000125 AC XY: 3 AN XY: 23946

African (AFR) AF: 0.00108 AC: 3 AN: 2782

American (AMR) AF: 0.00152 AC: 6 AN: 3938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 976

East Asian (EAS) AF: 0.00 AC: 0 AN: 3410

South Asian (SAS) AF: 0.00 AC: 0 AN: 7048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.000130 AC: 3 AN: 23066

Other (OTH) AF: 0.000876 AC: 2 AN: 2284

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.000299 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.9
DANN	Benign	0.58
PhyloP100		0.81
PromoterAI		0.0028	Neutral
Mutation Taster		=99/1	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: rs61735859; hg19: chr21-44480637;