21-43063958-G-A

Variant names:

• chr21-43063958-G-A
• rs758236584
• NM_000071.3:c.770C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.770C>T​(p.Thr257Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004847670: "In vitro functional studies support an impact on protein function" (Mayfield 2012, Yadav 2012, Sebastio 1995, Lee 2005)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T257T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 3)
  • Exomes 𝑓: 0.000040 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.70
• Publications: 21 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004847670: "In vitro functional studies support an impact on protein function" (Mayfield 2012, Yadav 2012, Sebastio 1995, Lee 2005).; SCV000249729: "Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 7762555, 16205833, 22977242)"; SCV000917110: "These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sebastio 1995, Lee 2005)."; SCV000649849: Experimental studies have shown that this missense change affects CBS function (PMID: 7762555, 16205833, 22267502, 22977242).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000071.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.997
• PP5: Variant 21-43063958-G-A is Pathogenic according to our data. Variant chr21-43063958-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.770C>T	p.Thr257Met	missense	Exon 9 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.770C>T	p.Thr257Met	missense	Exon 9 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.770C>T	p.Thr257Met	missense	Exon 9 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.770C>T	p.Thr257Met	missense	Exon 9 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.770C>T	p.Thr257Met	missense	Exon 9 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.770C>T	p.Thr257Met	missense	Exon 9 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 7924 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248606 AF XY: 0.0000520

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000399 AC: 8 AN: 200730 Hom.: 1 Cov.: 0 AF XY: 0.0000375 AC XY: 4 AN XY: 106574

African (AFR) AF: 0.000283 AC: 2 AN: 7070

American (AMR) AF: 0.000252 AC: 3 AN: 11922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5186

East Asian (EAS) AF: 0.00 AC: 0 AN: 21360

South Asian (SAS) AF: 0.0000361 AC: 1 AN: 27704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 794

European-Non Finnish (NFE) AF: 0.0000192 AC: 2 AN: 104182

Other (OTH) AF: 0.00 AC: 0 AN: 11278

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 7924 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 3534

African (AFR) AF: 0.00 AC: 0 AN: 1750

American (AMR) AF: 0.00 AC: 0 AN: 972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 132

East Asian (EAS) AF: 0.00 AC: 0 AN: 652

South Asian (SAS) AF: 0.00 AC: 0 AN: 316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2932

Other (OTH) AF: 0.00 AC: 0 AN: 118

Alfa AF: 0.0000336 Hom.: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Classic homocystinuria (5)
1	-	-	Homocystinuria (1)
1	-	-	Hyperhomocysteinemia (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
1	-	-	not provided (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		8.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Gain of MoRF binding (P = 0.0819)
MVP		0.94
MPC		1.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs758236584; hg19: chr21-44484068;