rs234712

Variant names:

• chr21-43067343-A-G
• rs234712
• NM_000071.3:c.317-966T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-43067343-A-G
• chr21-43067343-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.317-966T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212
• Publications: 6 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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.317-966T>C		intron	N/A	NP_000062.1
	CBS	NM_001178008.3		c.317-966T>C		intron	N/A	NP_001171479.1
	CBS	NM_001178009.3		c.317-966T>C		intron	N/A	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.317-966T>C		intron	N/A	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.317-966T>C		intron	N/A	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.317-966T>C		intron	N/A	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 132 AN: 11946 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.00436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00855

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00890

Gnomad OTH AF: 0.00543

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0110 AC: 132 AN: 11978 Hom.: 26 Cov.: 0 AF XY: 0.0107 AC XY: 66 AN XY: 6178

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00435 AC: 6 AN: 1378

American (AMR) AF: 0.0103 AC: 41 AN: 4000

Ashkenazi Jewish (ASJ) AF: 0.00855 AC: 2 AN: 234

East Asian (EAS) AF: 0.0507 AC: 21 AN: 414

South Asian (SAS) AF: 0.0360 AC: 17 AN: 472

European-Finnish (FIN) AF: 0.00518 AC: 4 AN: 772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00913 AC: 40 AN: 4380

Other (OTH) AF: 0.00538 AC: 1 AN: 186

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.944 Hom.: 53792

Asia WGS AF: 0.906 AC: 3153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.6
DANN	Benign	0.25
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs234712; hg19: chr21-44487453;