21-43065673-C-T

Variant names:

• chr21-43065673-C-T
• rs189362155
• NM_000071.3:c.474G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000398165.8(CBS):​c.474G>A​(p.Ala158Ala) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A158A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS ENST00000398165.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.66
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-43065673-C-T is Benign according to our data. Variant chr21-43065673-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.66 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398165.8. 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.474G>A	p.Ala158Ala	synonymous	Exon 6 of 17	NP_000062.1
	CBS	NM_001178008.3		c.474G>A	p.Ala158Ala	synonymous	Exon 6 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.474G>A	p.Ala158Ala	synonymous	Exon 6 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.474G>A	p.Ala158Ala	synonymous	Exon 6 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.474G>A	p.Ala158Ala	synonymous	Exon 6 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.474G>A	p.Ala158Ala	synonymous	Exon 6 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 1060 Hom.: 0 Cov.: 0

Gnomad AFR 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: 0.000137 AC: 24 AN: 175244 AF XY: 0.000150

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000553

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000558

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000444 AC: 12 AN: 270360 Hom.: 0 Cov.: 0 AF XY: 0.0000350 AC XY: 5 AN XY: 142738

African (AFR) AF: 0.00 AC: 0 AN: 8236

American (AMR) AF: 0.000293 AC: 4 AN: 13652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7516

East Asian (EAS) AF: 0.0000451 AC: 1 AN: 22178

South Asian (SAS) AF: 0.00 AC: 0 AN: 39528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1084

European-Non Finnish (NFE) AF: 0.0000406 AC: 6 AN: 147868

Other (OTH) AF: 0.0000660 AC: 1 AN: 15144

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1060 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 530

African (AFR) AF: 0.00 AC: 0 AN: 146

American (AMR) AF: 0.00 AC: 0 AN: 210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14

East Asian (EAS) AF: 0.00 AC: 0 AN: 196

South Asian (SAS) AF: 0.00 AC: 0 AN: 106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 352

Other (OTH) AF: 0.00 AC: 0 AN: 18

Alfa AF: 0.0000509 Hom.: 0

ClinVar

ClinVar submissions as Germline

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.16
DANN	Benign	0.59
PhyloP100		-6.7

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: rs189362155; hg19: chr21-44485783;