9-2643643-G-T

Variant names:

• chr9-2643643-G-T
• rs114307467
• NM_003383.5:c.836G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003383.5(VLDLR):​c.836G>T​(p.Arg279Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R279Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35
• Publications: 6 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.836G>T	p.Arg279Leu	missense	Exon 6 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.836G>T	p.Arg279Leu	missense	Exon 6 of 18	NP_001018066.1
	VLDLR	NM_001322225.2		c.713G>T	p.Arg238Leu	missense	Exon 5 of 18	NP_001309154.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.836G>T	p.Arg279Leu	missense	Exon 6 of 19	ENSP00000371532.2
	VLDLR	ENST00000382099.3	TSL:1	c.386G>T	p.Arg129Leu	missense	Exon 2 of 15	ENSP00000371531.3
	VLDLR	ENST00000947327.1		c.833G>T	p.Arg278Leu	missense	Exon 6 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.14	B
Vest4		0.69
MutPred		0.56		Loss of phosphorylation at T277 (P = 0.0724)
MVP		0.77
MPC		0.13
ClinPred		0.97	D
GERP RS		2.0
PromoterAI		-0.023	Neutral
Varity_R		0.32
gMVP		0.47
Mutation Taster		=78/22	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: rs114307467; hg19: chr9-2643643;