Genetic Variant VLDLR:c.-21_-19dupGGC (chr9-2622146-A-ACGG) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_003383.5(VLDLR):c.-21_-19dupGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.25 ( 5849 hom., cov: 0)

Exomes 𝑓: 0.29 ( 37238 hom. )

Consequence

VLDLR
NM_003383.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.20

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:

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

VLDLR-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-2622146-A-ACGG is Benign according to our data. Variant chr9-2622146-A-ACGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287823.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=2}.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5 link	c.-21_-19dupGGC		5_prime_UTR_variant	Exon 1 of 19	ENST00000382100.8	NP_003374.3	P98155-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100 link	c.-21_-19dupGGC		5_prime_UTR_variant	Exon 1 of 19	1	NM_003383.5	ENSP00000371532.2		P98155-1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38285

AN:

150414

Hom.:

5843

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0966

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.368

Gnomad EAS

AF:

0.0532

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.391

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.256

GnomAD3 exomes

AF:

0.302

AC:

15122

AN:

50120

Hom.:

1713

AF XY:

0.309

AC XY:

8680

AN XY:

28098

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.279

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.0615

Gnomad SAS exome

AF:

0.372

Gnomad FIN exome

AF:

0.391

Gnomad NFE exome

AF:

0.316

Gnomad OTH exome

AF:

0.283

GnomAD4 exome

AF:

0.293

AC:

361375

AN:

1234812

Hom.:

37238

Cov.:

AF XY:

0.296

AC XY:

179468

AN XY:

607236

show subpopulations

Gnomad4 AFR exome

AF:

0.0877

Gnomad4 AMR exome

AF:

0.248

Gnomad4 ASJ exome

AF:

0.329

Gnomad4 EAS exome

AF:

0.0443

Gnomad4 SAS exome

AF:

0.342

Gnomad4 FIN exome

AF:

0.346

Gnomad4 NFE exome

AF:

0.302

Gnomad4 OTH exome

AF:

0.280

GnomAD4 genome

AF:

0.254

AC:

38305

AN:

150524

Hom.:

5849

Cov.:

AF XY:

0.256

AC XY:

18827

AN XY:

73460

show subpopulations

Gnomad4 AFR

AF:

0.0964

Gnomad4 AMR

AF:

0.242

Gnomad4 ASJ

AF:

0.368

Gnomad4 EAS

AF:

0.0533

Gnomad4 SAS

AF:

0.366

Gnomad4 FIN

AF:

0.391

Gnomad4 NFE

AF:

0.330

Gnomad4 OTH

AF:

0.256

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

May 14, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital cerebellar hypoplasia

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

9-2622146-ACGGCGGCGGCGG-ACGGCGGCGGCGGCGG

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