9-2622019-G-C

Position:

• chr9-2622019-G-C

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.-171G>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 0.00612 in 656,412 control chromosomes in the GnomAD database, including 20 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 0.0058 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (16 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: -0.0510

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=-0.52).
• BP6: Variant 9-2622019-G-C is Benign according to our data. Variant chr9-2622019-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00577 (877/152054) while in subpopulation NFE AF= 0.0086 (584/67944). AF 95% confidence interval is 0.00802. There are 4 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.-171G>C		5_prime_UTR_variant	1/19	ENST00000382100.8	NP_003374.3
VLDLR-AS1	NR_015375.2	n.274+81C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.-171G>C		5_prime_UTR_variant	1/19	1	NM_003383.5	ENSP00000371532
VLDLR-AS1	ENST00000657742.1	n.274+81C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 878 AN: 151940 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00859

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00622 AC: 3139 AN: 504358 Hom.: 16 Cov.: 7 AF XY: 0.00600 AC XY: 1607 AN XY: 267614

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00777

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00577 AC: 877 AN: 152054 Hom.: 4 Cov.: 31 AF XY: 0.00596 AC XY: 443 AN XY: 74334

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.00860

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00309 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.000289 AC: 1 AN: 3474

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

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

VLDLR: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs35763266; hg19: chr9-2622019;