NM_000071.3:c.1039G>A

Variant names:

• chr21-43062311-C-T
• rs771298943
• NM_000071.3:c.1039G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000071.3(CBS):​c.1039G>A​(p.Gly347Ser) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249703: Published functional studies demonstrate that p.(G347S) is associated with very low levels of residual cystathionine beta-synthase enzyme activity compared to wild-type (PMID:12124992)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G347C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.85
• Publications: 10 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249703: Published functional studies demonstrate that p.(G347S) is associated with very low levels of residual cystathionine beta-synthase enzyme activity compared to wild-type (PMID: 12124992); SCV000917108: The most pronounced variant effect results in <10% of normal activity (Lee_2005).; SCV000937630: Experimental studies have shown that this missense change affects CBS function (PMID: 22267502).; SCV002701152: "In addition, this variant has been reported to result in absence of, or significantly reduced, enzyme activity in various expression systems, and was reported as non-functional in a yeast growth assay (Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Lee SJ et al. J. Hum. Genet., 2005 Oct;50:648-54)."
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 21-43062311-C-T is Pathogenic according to our data. Variant chr21-43062311-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 188801.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.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 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.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1039G>A	p.Gly347Ser	missense splice_region	Exon 11 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000427 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Classic homocystinuria (5)
3	-	-	not provided (3)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		6.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.96		Gain of sheet (P = 0.0827)
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
Splicevardb		2.0
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -4

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

Other links and lift over

dbSNP: rs771298943; hg19: chr21-44482421; COSMIC: COSV61442621; COSMIC: COSV61442621;