9-2622068-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003383.5(VLDLR):c.-122T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 129,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.130

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000388 (50/129022) while in subpopulation AFR AF= 0.00132 (47/35550). AF 95% confidence interval is 0.00102. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-122T>C		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.274+32A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-122T>C		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.274+32A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 50 AN: 128996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000345

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000687 AC: 38 AN: 552896 Hom.: 0 Cov.: 10 AF XY: 0.0000783 AC XY: 22 AN XY: 281080

Gnomad4 AFR exome AF: 0.000332

Gnomad4 AMR exome AF: 0.0000746

Gnomad4 ASJ exome AF: 0.000276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.000388 AC: 50 AN: 129022 Hom.: 0 Cov.: 31 AF XY: 0.000475 AC XY: 30 AN XY: 63218

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000120

Gnomad4 NFE AF: 0.0000345

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00691 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.81

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: rs886063802; hg19: chr9-2622068;