rs2219143

Positions:

• chr9-2622278-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003383.5(VLDLR):​c.82+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,478,472 control chromosomes in the GnomAD database, including 105,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8698 hom., cov: 32)
  • Exomes 𝑓: 0.38 (97057 hom.)
• Consequence: VLDLR NM_003383.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.36

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

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 9-2622278-G-A is Benign according to our data. Variant chr9-2622278-G-A is described in ClinVar as [Benign]. Clinvar id is 130713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2622278-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.82+7G>A		splice_region_variant, intron_variant		ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.96C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.82+7G>A		splice_region_variant, intron_variant		1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.96C>T		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47792 AN: 151782 Hom.: 8700 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.308

GnomAD3 exomes AF: 0.369 AC: 31466 AN: 85348 Hom.: 6215 AF XY: 0.356 AC XY: 17175 AN XY: 48230

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.455

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.377 AC: 499971 AN: 1326576 Hom.: 97057 Cov.: 36 AF XY: 0.373 AC XY: 243429 AN XY: 652982

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.415

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.350

GnomAD4 genome AF: 0.315 AC: 47802 AN: 151896 Hom.: 8698 Cov.: 32 AF XY: 0.316 AC XY: 23442 AN XY: 74254

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.311

Alfa AF: 0.380 Hom.: 10316

Bravo AF: 0.311

Asia WGS AF: 0.341 AC: 1185 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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	Genetic Services Laboratory, University of Chicago	Feb 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Congenital cerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2219143; hg19: chr9-2622278;