chr21-43056985-C-T

Variant names:

• chr21-43056985-C-T
• rs1005584
• NM_000071.3:c.1468-98G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The NM_000071.3(CBS):​c.1468-98G>A variant causes a intron 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 0.075 (49 hom., cov: 3)
  • Exomes 𝑓: 0.0032 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.00
• Publications: 5 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 -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 21-43056985-C-T is Benign according to our data. Variant chr21-43056985-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1468-98G>A		intron_variant	Intron 15 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1468-98G>A		intron_variant	Intron 15 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.0740 AC: 453 AN: 6124 Hom.: 48 Cov.: 3

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0500

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0270

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0887

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00320 AC: 67 AN: 20970 Hom.: 2 AF XY: 0.00338 AC XY: 39 AN XY: 11552

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

African (AFR) AF: 0.0233 AC: 2 AN: 86

American (AMR) AF: 0.00330 AC: 14 AN: 4244

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 1 AN: 446

East Asian (EAS) AF: 0.000729 AC: 1 AN: 1372

South Asian (SAS) AF: 0.00541 AC: 28 AN: 5176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 834

Middle Eastern (MID) AF: 0.0109 AC: 1 AN: 92

European-Non Finnish (NFE) AF: 0.00236 AC: 18 AN: 7630

Other (OTH) AF: 0.00183 AC: 2 AN: 1090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0748 AC: 458 AN: 6124 Hom.: 49 Cov.: 3 AF XY: 0.0708 AC XY: 205 AN XY: 2894

African (AFR) AF: 0.253 AC: 172 AN: 680

American (AMR) AF: 0.0260 AC: 42 AN: 1616

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 5 AN: 124

East Asian (EAS) AF: 0.119 AC: 62 AN: 520

South Asian (SAS) AF: 0.112 AC: 42 AN: 374

European-Finnish (FIN) AF: 0.0147 AC: 8 AN: 544

Middle Eastern (MID) AF: 0.0286 AC: 2 AN: 70

European-Non Finnish (NFE) AF: 0.0557 AC: 113 AN: 2030

Other (OTH) AF: 0.0794 AC: 10 AN: 126

Alfa AF: 0.0668 Hom.: 761

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	19
DANN	Benign	0.85
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1005584; hg19: chr21-44477095;