rs1347662650

chr21-43068541-A-Gchr21-43068541-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_000071.3(CBS):c.284T>C(p.Ile95Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. I95N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 6)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43068541-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2908113.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 21-43068541-A-G is Pathogenic according to our data. Variant chr21-43068541-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471361.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.284T>C	p.Ile95Thr	missense_variant	4/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.284T>C	p.Ile95Thr	missense_variant	4/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 4 AN: 355624 Hom.: 0 Cov.: 0 AF XY: 0.00000522 AC XY: 1 AN XY: 191474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000442

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000365

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000071.2(CBS):c.284T>C(I95T) is a missense variant classified as a variant of uncertain significance in the context of homocystinuria, CBS-related. I95T has been observed in a case with relevant disease (PMID: 29352562). Functional assessments of this variant are available in the literature (PMID: 29352562, 20455263). I95T has been observed in population frequency databases (gnomAD: AMR <0.002%). In summary, there is insufficient evidence to classify NM_000071.2(CBS):c.284T>C(I95T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 20, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 17, 2023	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 95 of the CBS protein (p.Ile95Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with homocystinuria (PMID: 29352562; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 471361). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 29352562). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.91
MutPred		0.83		Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);
MVP		0.89
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1347662650; hg19: chr21-44488651;