9-2622146-ACGGCGGCGGCGG-ACGG

Variant names:

• chr9-2622146-ACGGCGGCGG-A
• rs71329437
• ENST00000453601.5:n.219_227delCCGCCGCCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000453601.5(VLDLR-AS1):​n.219_227delCCGCCGCCG 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 0.375 in 1,386,978 control chromosomes in the GnomAD database, including 94,983 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.33 (8761 hom., cov: 0)
  • Exomes 𝑓: 0.38 (86222 hom.)
• Consequence: VLDLR-AS1 ENST00000453601.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.45
• Publications: 3 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 -9 ACMG points.

• BP6: Variant 9-2622146-ACGGCGGCGG-A is Benign according to our data. Variant chr9-2622146-ACGGCGGCGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290493.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.-27_-19delGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 19	ENST00000382100.8	NP_003374.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.-27_-19delGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 19	1	NM_003383.5	ENSP00000371532.2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49501 AN: 150360 Hom.: 8751 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.302 AC: 15135 AN: 50120 AF XY: 0.293

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.380 AC: 469971 AN: 1236508 Hom.: 86222 AF XY: 0.375 AC XY: 227489 AN XY: 606996

African (AFR) AF: 0.194 AC: 4989 AN: 25658

American (AMR) AF: 0.397 AC: 9447 AN: 23794

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 6016 AN: 20152

East Asian (EAS) AF: 0.414 AC: 12290 AN: 29714

South Asian (SAS) AF: 0.235 AC: 15153 AN: 64504

European-Finnish (FIN) AF: 0.383 AC: 11574 AN: 30240

Middle Eastern (MID) AF: 0.281 AC: 1427 AN: 5078

European-Non Finnish (NFE) AF: 0.396 AC: 390612 AN: 985518

Other (OTH) AF: 0.356 AC: 18463 AN: 51850

GnomAD4 genome AF: 0.329 AC: 49548 AN: 150470 Hom.: 8761 Cov.: 0 AF XY: 0.330 AC XY: 24225 AN XY: 73448

African (AFR) AF: 0.198 AC: 8132 AN: 41054

American (AMR) AF: 0.414 AC: 6289 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1031 AN: 3460

East Asian (EAS) AF: 0.420 AC: 2085 AN: 4962

South Asian (SAS) AF: 0.238 AC: 1136 AN: 4764

European-Finnish (FIN) AF: 0.360 AC: 3734 AN: 10386

Middle Eastern (MID) AF: 0.348 AC: 101 AN: 290

European-Non Finnish (NFE) AF: 0.388 AC: 26168 AN: 67366

Other (OTH) AF: 0.333 AC: 699 AN: 2096

Alfa AF: 0.260 Hom.: 675

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital cerebellar hypoplasia Uncertain:1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

- -

not specified Benign:1

Aug 17, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71329437; hg19: chr9-2622146; COSMIC: COSV105314195; COSMIC: COSV105314195;