NM_000071.3:c.435G>T

Variant names:

• chr21-43066259-C-A
• rs148782895
• NM_000071.3:c.435G>T
• CBS p.Pro145Pro

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000071.3(CBS):​c.435G>T​(p.Pro145Pro) 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 (★). Synonymous variant affecting the same amino acid position (i.e. P145P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.380
• 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, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 21-43066259-C-A is Benign according to our data. Variant chr21-43066259-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2768240.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.38 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.435G>T	p.Pro145Pro	synonymous	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.435G>T	p.Pro145Pro	synonymous	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.435G>T	p.Pro145Pro	synonymous	Exon 5 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.435G>T	p.Pro145Pro	synonymous	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.435G>T	p.Pro145Pro	synonymous	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.435G>T	p.Pro145Pro	synonymous	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1216376 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 609004

African (AFR) AF: 0.00 AC: 0 AN: 18864

American (AMR) AF: 0.00 AC: 0 AN: 42416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21968

East Asian (EAS) AF: 0.00 AC: 0 AN: 38826

South Asian (SAS) AF: 0.00 AC: 0 AN: 76442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4386

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 922562

Other (OTH) AF: 0.00 AC: 0 AN: 51042

GnomAD4 genome Cov.: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.47
DANN	Benign	0.70
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs148782895;

hg19: chr21-44486369;