9-2622134-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003383.5(VLDLR):c.-56C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,441,502 control chromosomes in the GnomAD database, including 95,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8164 hom., cov: 30)
  • Exomes 𝑓: 0.36 (87721 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.127

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-2622134-C-T is Benign according to our data. Variant chr9-2622134-C-T is described in ClinVar as [Benign]. Clinvar id is 366354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-56C>T		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.240G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-56C>T		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.240G>A		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.317 AC: 46792 AN: 147390 Hom.: 8166 Cov.: 30

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.325

GnomAD4 exome AF: 0.362 AC: 468011 AN: 1294016 Hom.: 87721 Cov.: 22 AF XY: 0.357 AC XY: 226931 AN XY: 636032

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.405

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.317 AC: 46805 AN: 147486 Hom.: 8164 Cov.: 30 AF XY: 0.318 AC XY: 22879 AN XY: 71926

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.283

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.328

Alfa AF: 0.343 Hom.: 4759

Bravo AF: 0.311

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital cerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 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	-0.47
Cadd	Benign	17
Dann	Benign	0.97

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: rs34881325; hg19: chr9-2622134; COSMIC: COSV66073719; COSMIC: COSV66073719;