Genetic Variant NM_003383.5:c.71C>G (chr9-2622260-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003383.5(VLDLR):c.71C>G(p.Ala24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. A24D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

VLDLR
NM_003383.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

0 publications found

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]

VLDLR links:

VLDLR-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

VLDLR-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26829803).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VLDLR	NM_003383.5	MANE Select	c.71C>G	p.Ala24Gly	missense	Exon 1 of 19	NP_003374.3
VLDLR	NM_001018056.3		c.71C>G	p.Ala24Gly	missense	Exon 1 of 18	NP_001018066.1
VLDLR	NM_001322225.2		c.71C>G	p.Ala24Gly	missense	Exon 1 of 18	NP_001309154.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.71C>G	p.Ala24Gly	missense	Exon 1 of 19	ENSP00000371532.2
VLDLR-AS1	ENST00000453601.5	TSL:1	n.114G>C		non_coding_transcript_exon	Exon 1 of 4
VLDLR	ENST00000681306.1		c.71C>G	p.Ala24Gly	missense	Exon 1 of 18	ENSP00000506072.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1339186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659994

show subpopulations

African (AFR)

AF:

0.0000366

AC:

AN:

27350

American (AMR)

AF:

0.00

AC:

AN:

30732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23640

East Asian (EAS)

AF:

0.00

AC:

AN:

30798

South Asian (SAS)

AF:

0.00

AC:

AN:

73762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059146

Other (OTH)

AF:

0.00

AC:

AN:

55978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.0018

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.0

PhyloP100

2.4

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.86

REVEL

Benign

0.26

Sift

Uncertain

0.016

Sift4G

Benign

0.27

Polyphen

0.0010

Vest4

0.13

MutPred

0.35

Loss of stability (P = 0.0781)

MVP

0.78

MPC

0.10

ClinPred

0.31

GERP RS

4.2

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.26

gMVP

0.17

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over