NM_000071.3:c.1451A>T

Variant names:

• chr21-43058161-T-A
• rs1555871913
• NM_000071.3:c.1451A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000071.3(CBS):​c.1451A>T​(p.Tyr484Phe) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y484C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.89

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1451A>T	p.Tyr484Phe	missense_variant	Exon 15 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1451A>T	p.Tyr484Phe	missense_variant	Exon 15 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Mar 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y484F variant (also known as c.1451A>T), located in coding exon 13 of the CBS gene, results from an A to T substitution at nucleotide position 1451. The tyrosine at codon 484 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine with phenylalanine at codon 484 of the CBS protein (p.Tyr484Phe). The tyrosine residue is moderately conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CBS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Uncertain	0.57	D;D;D;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.8	L;L;L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.027	B;B;B;B
Vest4		0.63
MutPred		0.53		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.62
MPC		0.32
ClinPred		0.44	T
GERP RS		4.6
Varity_R		0.50
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1555871913; hg19: chr21-44478271;