9-2646516-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003383.5(VLDLR):​c.1667G>C​(p.Arg556Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R556Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

VLDLR
NM_003383.5 missense

Scores

6
7
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.57
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VLDLRNM_003383.5 linkc.1667G>C p.Arg556Pro missense_variant Exon 11 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.1667G>C p.Arg556Pro missense_variant Exon 11 of 19 1 NM_003383.5 ENSP00000371532.2 P98155-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461854
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;.
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Benign
0.97
L;L
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.3
N;N
REVEL
Pathogenic
0.70
Sift
Uncertain
0.028
D;D
Sift4G
Benign
0.12
T;T
Polyphen
0.13
B;P
Vest4
0.76
MutPred
0.72
Gain of glycosylation at S560 (P = 0.0843);Gain of glycosylation at S560 (P = 0.0843);
MVP
0.89
MPC
0.51
ClinPred
0.71
D
GERP RS
4.6
Varity_R
0.52
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr9-2646516; API