rs749697783

Variant names:

• chr21-43068528-G-A
• rs749697783
• NM_000071.3:c.297C>T
• CBS p.Phe99Phe

Your query was ambiguous. Multiple possible variants found:

• chr21-43068528-G-A
• chr21-43068528-G-C

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.297C>T​(p.Phe99Phe) 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 6)
  • Exomes 𝑓: 0.000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.557
• Publications: 3 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, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 21-43068528-G-A is Benign according to our data. Variant chr21-43068528-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 519588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.557 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.297C>T	p.Phe99Phe	synonymous	Exon 4 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.297C>T	p.Phe99Phe	synonymous	Exon 4 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.297C>T	p.Phe99Phe	synonymous	Exon 4 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.297C>T	p.Phe99Phe	synonymous	Exon 4 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.297C>T	p.Phe99Phe	synonymous	Exon 4 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.297C>T	p.Phe99Phe	synonymous	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0000258 AC: 1 AN: 38818 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251346 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000149 AC: 5 AN: 336350 Hom.: 0 Cov.: 0 AF XY: 0.0000110 AC XY: 2 AN XY: 181038

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

African (AFR) AF: 0.00 AC: 0 AN: 8856

American (AMR) AF: 0.00 AC: 0 AN: 22498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11236

East Asian (EAS) AF: 0.00 AC: 0 AN: 26496

South Asian (SAS) AF: 0.0000698 AC: 3 AN: 43000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1410

European-Non Finnish (NFE) AF: 0.0000109 AC: 2 AN: 183970

Other (OTH) AF: 0.00 AC: 0 AN: 18624

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0191254), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000257 AC: 1 AN: 38906 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 17816

African (AFR) AF: 0.00 AC: 0 AN: 8198

American (AMR) AF: 0.00 AC: 0 AN: 5202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1132

East Asian (EAS) AF: 0.000566 AC: 1 AN: 1766

South Asian (SAS) AF: 0.00 AC: 0 AN: 968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18310

Other (OTH) AF: 0.00 AC: 0 AN: 514

Alfa AF: 0.0000709 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.39
DANN	Benign	0.73
PhyloP100		0.56

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749697783;

hg19: chr21-44488638;

COSMIC: COSV61442202;

COSMIC: COSV61442202;