21-43067294-T-C

Position:

• chr21-43067294-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.317-917A>G 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 0.37 (2039 hom., cov: 4)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.317-917A>G		intron_variant		ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.317-917A>G		intron_variant		1	NM_000071.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 6650 AN: 17990 Hom.: 2036 Cov.: 4 FAILED QC

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.288

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: 0.369 AC: 6651 AN: 18006 Hom.: 2039 Cov.: 4 AF XY: 0.338 AC XY: 2899 AN XY: 8576

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.280

Alfa AF: 0.563 Hom.: 37921

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs2851391; hg19: chr21-44487404; COSMIC: COSV61445871; COSMIC: COSV61445871;