9-2651454-C-T

Position:

chr9-2651454-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The ENST00000382100.8(VLDLR):c.2291C>T(p.Thr764Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T764T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

VLDLR
ENST00000382100.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.06

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:

LOC105375957 (HGNC:):

LOC105375957 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007685244).

BP6

Variant 9-2651454-C-T is Benign according to our data. Variant chr9-2651454-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2651454-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (374/152222) while in subpopulation AFR AF= 0.00713 (296/41540). AF 95% confidence interval is 0.00646. There are 0 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VLDLR	NM_003383.5 linkuse as main transcript	c.2291C>T	p.Thr764Met	missense_variant	16/19	ENST00000382100.8	NP_003374.3
LOC105375957	XR_929436.3 linkuse as main transcript	n.28188G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8 linkuse as main transcript	c.2291C>T	p.Thr764Met	missense_variant	16/19	1	NM_003383.5	ENSP00000371532		P98155-1

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00715

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00120

AC:

302

AN:

250652

Hom.:

AF XY:

0.00103

AC XY:

140

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.00900

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000558

AC:

816

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

366

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00830

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000278

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00246

AC:

374

AN:

152222

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00713

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000471

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00130

AC:

158

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	VLDLR: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

VLDLR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.73

M_CAP

Benign

0.049

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

REVEL

Benign

0.26

Sift

Benign

0.051

Sift4G

Benign

0.12

Polyphen

0.61

Vest4

0.47

MVP

0.83

MPC

0.12

ClinPred

0.015

GERP RS

3.1

Varity_R

0.030

gMVP

0.49

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over