9-2650382-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_003383.5(VLDLR):​c.2117G>T​(p.Cys706Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

VLDLR
NM_003383.5 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.57
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 9-2650382-G-T is Pathogenic according to our data. Variant chr9-2650382-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 64373.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VLDLRNM_003383.5 linkc.2117G>T p.Cys706Phe missense_variant Exon 15 of 19 ENST00000382100.8 NP_003374.3 P98155-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VLDLRENST00000382100.8 linkc.2117G>T p.Cys706Phe missense_variant Exon 15 of 19 1 NM_003383.5 ENSP00000371532.2 P98155-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cerebellar hypoplasia Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PS3,PM3 (strong), PP3,PM2 -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Pathogenic:1
Sep 14, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.5
H;H
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-10
D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.82
Loss of ubiquitination at K703 (P = 0.1066);Loss of ubiquitination at K703 (P = 0.1066);
MVP
0.92
MPC
0.57
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.97
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514750; hg19: chr9-2650382; COSMIC: COSV66078411; COSMIC: COSV66078411; API