rs754246295

Variant names:

• chr21-43065646-G-A
• rs754246295
• NM_000071.3:c.501C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43065646-G-A
• chr21-43065646-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000071.3(CBS):​c.501C>T​(p.Ile167Ile) 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: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000030 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.161
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 21-43065646-G-A is Benign according to our data. Variant chr21-43065646-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 381476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.161 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.501C>T	p.Ile167Ile	synonymous	Exon 6 of 17	NP_000062.1
	CBS	NM_001178008.3		c.501C>T	p.Ile167Ile	synonymous	Exon 6 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.501C>T	p.Ile167Ile	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.501C>T	p.Ile167Ile	synonymous	Exon 6 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.501C>T	p.Ile167Ile	synonymous	Exon 6 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.501C>T	p.Ile167Ile	synonymous	Exon 6 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 1282 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: 0.0000375 AC: 7 AN: 186604 AF XY: 0.0000200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000141

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000302 AC: 9 AN: 298174 Hom.: 3 Cov.: 0 AF XY: 0.0000127 AC XY: 2 AN XY: 157150

African (AFR) AF: 0.00 AC: 0 AN: 9146

American (AMR) AF: 0.000344 AC: 5 AN: 14550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8468

East Asian (EAS) AF: 0.00 AC: 0 AN: 25468

South Asian (SAS) AF: 0.0000494 AC: 2 AN: 40504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1236

European-Non Finnish (NFE) AF: 0.0000122 AC: 2 AN: 164248

Other (OTH) AF: 0.00 AC: 0 AN: 17022

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1282 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 640

African (AFR) AF: 0.00 AC: 0 AN: 212

American (AMR) AF: 0.00 AC: 0 AN: 220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20

East Asian (EAS) AF: 0.00 AC: 0 AN: 232

South Asian (SAS) AF: 0.00 AC: 0 AN: 120

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: 438

Other (OTH) AF: 0.00 AC: 0 AN: 22

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	-0.38
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.16

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: rs754246295; hg19: chr21-44485756;