9-2622077-C-G

Position:

• chr9-2622077-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003383.5(VLDLR):​c.-113C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,074,310 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 31)
  • Exomes 𝑓: 0.016 (211 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.268

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-2622077-C-G is Benign according to our data. Variant chr9-2622077-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366350.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1728/151894) while in subpopulation NFE AF= 0.0179 (1216/67874). AF 95% confidence interval is 0.0171. There are 13 homozygotes in gnomad4. There are 795 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-113C>G		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.274+23G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-113C>G		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.274+23G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1729 AN: 151784 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0163 AC: 15019 AN: 922416 Hom.: 211 Cov.: 12 AF XY: 0.0160 AC XY: 7412 AN XY: 461994

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00567

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000373

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0114 AC: 1728 AN: 151894 Hom.: 13 Cov.: 31 AF XY: 0.0107 AC XY: 795 AN XY: 74240

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0113

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00581 Hom.: 2

Bravo AF: 0.0106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital cerebellar hypoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2018

- -

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

Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs34433332; hg19: chr9-2622077;