rs1554621358

Variant names:

• chr9-2644817-G-A
• rs1554621358
• NM_003383.5:c.1150G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-2644817-G-A
• chr9-2644817-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003383.5(VLDLR):​c.1150G>A​(p.Ala384Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A384A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91
• Publications: 0 publications found

Genes affected

VLDLR (HGNC:12698): (very low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. This gene encodes a lipoprotein receptor that is a member of the LDLR family and plays important roles in VLDL-triglyceride metabolism and the reelin signaling pathway. Mutations in this gene cause VLDLR-associated cerebellar hypoplasia. Alternative splicing generates multiple transcript variants encoding distinct isoforms for this gene. [provided by RefSeq, Aug 2009]

VLDLR Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.1150G>A	p.Ala384Thr	missense	Exon 8 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.1150G>A	p.Ala384Thr	missense	Exon 8 of 18	NP_001018066.1
	VLDLR	NM_001322225.2		c.1027G>A	p.Ala343Thr	missense	Exon 7 of 18	NP_001309154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.1150G>A	p.Ala384Thr	missense	Exon 8 of 19	ENSP00000371532.2
	VLDLR	ENST00000382099.3	TSL:1	c.706G>A	p.Ala236Thr	missense	Exon 4 of 15	ENSP00000371531.3
	VLDLR	ENST00000681306.1		c.1150G>A	p.Ala384Thr	missense	Exon 8 of 18	ENSP00000506072.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.78	N
PhyloP100		4.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.39
Sift	Benign	0.49	T
Sift4G	Benign	0.27	T
Polyphen		0.96	D
Vest4		0.46
MutPred		0.59		Loss of sheet (P = 0.1907)
MVP		0.89
MPC		0.30
ClinPred		0.63	D
GERP RS		5.8
Varity_R		0.092
gMVP		0.13
Mutation Taster		=67/33	polymorphism

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: rs1554621358; hg19: chr9-2644817;