rs28934891

Variant names:

• chr21-43058862-C-G
• NM_000071.3:c.1330G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-43058862-C-G
• chr21-43058862-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000071.3(CBS):​c.1330G>C​(p.Asp444His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D444N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 6 ACMG points.

• PM1: In a domain CBS (size 58) in uniprot entity CBS_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43058862-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1330G>C	p.Asp444His	missense_variant	Exon 14 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1330G>C	p.Asp444His	missense_variant	Exon 14 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.71	P;P;P;P
Vest4		0.93
MutPred		0.67		Loss of ubiquitination at K441 (P = 0.0618);Loss of ubiquitination at K441 (P = 0.0618);Loss of ubiquitination at K441 (P = 0.0618);Loss of ubiquitination at K441 (P = 0.0618);
MVP		0.90
MPC		0.96
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.87

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-44478972;