9-2648747-C-T

Position:

• chr9-2648747-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003383.5(VLDLR):​c.2041C>T​(p.Leu681Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0079 in 1,614,162 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (93 hom.)
• Consequence: VLDLR NM_003383.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.68

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 9-2648747-C-T is Benign according to our data. Variant chr9-2648747-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130706.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr9-2648747-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00546 (831/152290) while in subpopulation SAS AF= 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 5 homozygotes in gnomad4. There are 395 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.2041C>T	p.Leu681Leu	synonymous_variant	14/19	ENST00000382100.8	NP_003374.3
VLDLR	NM_001018056.3	c.2041C>T	p.Leu681Leu	synonymous_variant	14/18		NP_001018066.1
VLDLR	NM_001322225.2	c.1918C>T	p.Leu640Leu	synonymous_variant	13/18		NP_001309154.1
VLDLR	NM_001322226.2	c.1918C>T	p.Leu640Leu	synonymous_variant	13/17		NP_001309155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.2041C>T	p.Leu681Leu	synonymous_variant	14/19	1	NM_003383.5	ENSP00000371532.2

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00693 AC: 1741 AN: 251352 Hom.: 20 AF XY: 0.00795 AC XY: 1080 AN XY: 135836

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00881

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00815 AC: 11921 AN: 1461872 Hom.: 93 Cov.: 32 AF XY: 0.00848 AC XY: 6164 AN XY: 727238

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00860

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00530 AC XY: 395 AN XY: 74462

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00870

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00725 Hom.: 3

Bravo AF: 0.00547

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.00948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VLDLR: BP4, BS1, BS2 -

Congenital cerebellar hypoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

VLDLR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as 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
BayesDel_noAF	Benign	-0.22
CADD	Benign	8.6
DANN	Benign	0.79

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

Other links and lift over

dbSNP: rs79720897; hg19: chr9-2648747;