9-2622278-G-A

Variant names:

• chr9-2622278-G-A
• rs2219143
• ENST00000453601.5:n.96C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000453601.5(VLDLR-AS1):​n.96C>T variant causes a non coding transcript exon 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. 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-AS1 ENST00000453601.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.36
• Publications: 18 publications found

Genes affected

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

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 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.82+7G>A		splice_region_variant, intron_variant	Intron 1 of 18	ENST00000382100.8	NP_003374.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.82+7G>A		splice_region_variant, intron_variant	Intron 1 of 18	1	NM_003383.5	ENSP00000371532.2

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

GnomAD2 exomes AF: 0.369 AC: 31466 AN: 85348 AF XY: 0.356

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 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

African (AFR) AF: 0.116 AC: 3142 AN: 26976

American (AMR) AF: 0.427 AC: 12408 AN: 29028

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 6919 AN: 23348

East Asian (EAS) AF: 0.364 AC: 10919 AN: 29978

South Asian (SAS) AF: 0.225 AC: 16337 AN: 72468

European-Finnish (FIN) AF: 0.415 AC: 13621 AN: 32802

Middle Eastern (MID) AF: 0.283 AC: 1220 AN: 4308

European-Non Finnish (NFE) AF: 0.395 AC: 416058 AN: 1052330

Other (OTH) AF: 0.350 AC: 19347 AN: 55338

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

African (AFR) AF: 0.129 AC: 5358 AN: 41514

American (AMR) AF: 0.398 AC: 6082 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1933 AN: 5078

South Asian (SAS) AF: 0.222 AC: 1066 AN: 4810

European-Finnish (FIN) AF: 0.396 AC: 4191 AN: 10586

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27212 AN: 67834

Other (OTH) AF: 0.311 AC: 658 AN: 2114

Alfa AF: 0.371 Hom.: 12911

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

Oct 31, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 11, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Congenital cerebellar hypoplasia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		2.4
PromoterAI		0.098	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2219143; hg19: chr9-2622278;