rs1801181

Variant names:

• chr21-43060506-G-A
• rs1801181
• NM_000071.3:c.1080C>T

Variant summary

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

The NM_000071.3(CBS):​c.1080C>T​(p.Ala360Ala) 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (0 hom., cov: 0)
  • Exomes 𝑓: 0.38 (3618 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: -2.38
• Publications: 49 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.009).
• BP6: Variant 21-43060506-G-A is Benign according to our data. Variant chr21-43060506-G-A is described in ClinVar as Benign. ClinVar VariationId is 92424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 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.1080C>T	p.Ala360Ala	synonymous	Exon 12 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1080C>T	p.Ala360Ala	synonymous	Exon 12 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1080C>T	p.Ala360Ala	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.1080C>T	p.Ala360Ala	synonymous	Exon 12 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1080C>T	p.Ala360Ala	synonymous	Exon 12 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1080C>T	p.Ala360Ala	synonymous	Exon 12 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 1 AN: 14 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad SAS AF: 0.167

Gnomad NFE AF: 0.00

GnomAD2 exomes AF: 0.334 AC: 80942 AN: 242274 AF XY: 0.344

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.614

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.345

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.382 AC: 15726 AN: 41214 Hom.: 3618 Cov.: 0 AF XY: 0.382 AC XY: 8379 AN XY: 21958

African (AFR) AF: 0.0571 AC: 152 AN: 2660

American (AMR) AF: 0.212 AC: 802 AN: 3778

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 342 AN: 898

East Asian (EAS) AF: 0.609 AC: 1772 AN: 2908

South Asian (SAS) AF: 0.342 AC: 2211 AN: 6474

European-Finnish (FIN) AF: 0.524 AC: 553 AN: 1056

Middle Eastern (MID) AF: 0.356 AC: 62 AN: 174

European-Non Finnish (NFE) AF: 0.423 AC: 8956 AN: 21174

Other (OTH) AF: 0.419 AC: 876 AN: 2092

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.167 AC: 1 AN: 6

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.333 Hom.: 3603

Asia WGS AF: 0.419 AC: 1458 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.355

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Classic homocystinuria (6)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	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	-0.79
CADD	Benign	0.12
DANN	Benign	0.59
PhyloP100		-2.4
PromoterAI		-0.026	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs1801181; hg19: chr21-44480616; COSMIC: COSV61441401; COSMIC: COSV61441401;