rs117687681

Variant names:

• chr21-43060481-G-A
• rs117687681
• NM_000071.3:c.1105C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 4P and 7B. PM1 PP2 PP3 BP4_Moderate BS1 BS2_Supporting

The NM_000071.3(CBS):​c.1105C>T​(p.Arg369Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:2 O:1
• Conservation: PhyloP100: 6.40
• Publications: 35 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.14451393).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00426 (180/42276) while in subpopulation MID AF = 0.00595 (1/168). AF 95% confidence interval is 0.00509. There are 5 homozygotes in GnomAdExome4. There are 83 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1105C>T	p.Arg369Cys	missense	Exon 12 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1105C>T	p.Arg369Cys	missense	Exon 12 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1105C>T	p.Arg369Cys	missense	Exon 12 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.1105C>T	p.Arg369Cys	missense	Exon 12 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1105C>T	p.Arg369Cys	missense	Exon 12 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1105C>T	p.Arg369Cys	missense	Exon 12 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 68 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad NFE AF: 0.00

GnomAD2 exomes AF: 0.00307 AC: 758 AN: 246960 AF XY: 0.00296

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00689

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00426 AC: 180 AN: 42276 Hom.: 5 Cov.: 0 AF XY: 0.00367 AC XY: 83 AN XY: 22632

African (AFR) AF: 0.00167 AC: 4 AN: 2402

American (AMR) AF: 0.00355 AC: 13 AN: 3664

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 12 AN: 952

East Asian (EAS) AF: 0.00 AC: 0 AN: 2746

South Asian (SAS) AF: 0.00 AC: 0 AN: 6952

European-Finnish (FIN) AF: 0.00487 AC: 6 AN: 1232

Middle Eastern (MID) AF: 0.00595 AC: 1 AN: 168

European-Non Finnish (NFE) AF: 0.00591 AC: 130 AN: 21982

Other (OTH) AF: 0.00643 AC: 14 AN: 2178

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 70 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 40

African (AFR) AF: 0.00 AC: 0 AN: 22

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 14

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 16

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.00417 Hom.: 6

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	8	-	Classic homocystinuria (8)
-	5	1	not provided (7)
-	1	-	Cardiovascular phenotype (1)
-	1	-	CBS-related disorder (1)
-	-	1	Congenital myopathy (1)
-	1	-	Connective tissue disorder (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.14	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.93
MPC		1.3
ClinPred		0.029	T
GERP RS		4.9
PromoterAI		-0.0046	Neutral
Varity_R		0.84
gMVP		0.88
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs117687681; hg19: chr21-44480591;