rs376011228

Variant names:

• chr21-43065278-TAGAA-T
• rs376011228
• NM_000071.3:c.667-10_667-7delTTCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000071.3(CBS):​c.667-10_667-7delTTCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,359,468 control chromosomes in the GnomAD database, including 28 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (13 hom., cov: 15)
  • Exomes 𝑓: 0.000082 (15 hom.)
• Consequence: CBS NM_000071.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.238
• 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: ClinGen, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 21-43065278-TAGAA-T is Benign according to our data. Variant chr21-43065278-TAGAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 405377.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000919 (111/120832) while in subpopulation AFR AF = 0.0032 (107/33474). AF 95% confidence interval is 0.00271. There are 13 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 15. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.667-10_667-7delTTCT		splice_region intron	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.667-10_667-7delTTCT		splice_region intron	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.667-10_667-7delTTCT		splice_region intron	N/A	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.667-10_667-7delTTCT		splice_region intron	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.667-10_667-7delTTCT		splice_region intron	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.667-10_667-7delTTCT		splice_region intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.000870 AC: 105 AN: 120704 Hom.: 13 Cov.: 15

Gnomad AFR AF: 0.00303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000247

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: 0.000627

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251350 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000815 AC: 101 AN: 1238636 Hom.: 15 AF XY: 0.0000726 AC XY: 45 AN XY: 619556

African (AFR) AF: 0.00233 AC: 72 AN: 30878

American (AMR) AF: 0.000141 AC: 6 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 79020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48640

Middle Eastern (MID) AF: 0.000401 AC: 2 AN: 4984

European-Non Finnish (NFE) AF: 0.0000109 AC: 10 AN: 917624

Other (OTH) AF: 0.000209 AC: 11 AN: 52714

GnomAD4 genome AF: 0.000919 AC: 111 AN: 120832 Hom.: 13 Cov.: 15 AF XY: 0.000991 AC XY: 58 AN XY: 58550

African (AFR) AF: 0.00320 AC: 107 AN: 33474

American (AMR) AF: 0.000246 AC: 3 AN: 12180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2790

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 3646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53058

Other (OTH) AF: 0.000618 AC: 1 AN: 1618

Alfa AF: 0.000427 Hom.: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Classic homocystinuria (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	Intellectual disability (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24

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: rs376011228; hg19: chr21-44485388;