rs539670390

Variant names:

• chr21-43065441-C-A
• rs539670390
• NM_000071.3:c.612G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43065441-C-A
• chr21-43065441-C-G
• chr21-43065441-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000071.3(CBS):​c.612G>T​(p.Val204Val) 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. V204V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000041 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.01
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 21-43065441-C-A is Benign according to our data. Variant chr21-43065441-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340086.
• BP7: Synonymous conserved (PhyloP=-1.01 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.612G>T	p.Val204Val	synonymous	Exon 7 of 17	NP_000062.1
	CBS	NM_001178008.3		c.612G>T	p.Val204Val	synonymous	Exon 7 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.612G>T	p.Val204Val	synonymous	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.612G>T	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.612G>T	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.612G>T	p.Val204Val	synonymous	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.0000508 AC: 1 AN: 19692 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000984

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: 0.0000960 AC: 24 AN: 249874 AF XY: 0.0000887

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000871

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000413 AC: 18 AN: 436228 Hom.: 1 Cov.: 0 AF XY: 0.0000430 AC XY: 10 AN XY: 232658

African (AFR) AF: 0.00 AC: 0 AN: 13626

American (AMR) AF: 0.00 AC: 0 AN: 30538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14582

East Asian (EAS) AF: 0.000351 AC: 11 AN: 31332

South Asian (SAS) AF: 0.0000562 AC: 3 AN: 53412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27710

Middle Eastern (MID) AF: 0.000530 AC: 1 AN: 1888

European-Non Finnish (NFE) AF: 0.00000838 AC: 2 AN: 238708

Other (OTH) AF: 0.0000409 AC: 1 AN: 24432

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000506 AC: 1 AN: 19764 Hom.: 0 Cov.: 5 AF XY: 0.000107 AC XY: 1 AN XY: 9334

African (AFR) AF: 0.00 AC: 0 AN: 4838

American (AMR) AF: 0.00 AC: 0 AN: 2130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 540

East Asian (EAS) AF: 0.000992 AC: 1 AN: 1008

South Asian (SAS) AF: 0.00 AC: 0 AN: 368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9038

Other (OTH) AF: 0.00 AC: 0 AN: 220

Alfa AF: 0.0000484 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-1.0

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: rs539670390; hg19: chr21-44485551;