9-2622121-A-G

Position:

• chr9-2622121-A-G

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.-69A>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 0.772 in 1,400,890 control chromosomes in the GnomAD database, including 419,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50035 hom., cov: 27)
  • Exomes 𝑓: 0.77 (369826 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.10

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=-0.53).
• BP6: Variant 9-2622121-A-G is Benign according to our data. Variant chr9-2622121-A-G is described in ClinVar as [Benign]. Clinvar id is 366352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-69A>G		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.253T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-69A>G		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.253T>C		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.811 AC: 122410 AN: 150928 Hom.: 49978 Cov.: 27

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.692

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.794

GnomAD4 exome AF: 0.767 AC: 958558 AN: 1249854 Hom.: 369826 Cov.: 18 AF XY: 0.761 AC XY: 468656 AN XY: 615814

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.851

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.822

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.772

Gnomad4 OTH exome AF: 0.761

GnomAD4 genome AF: 0.811 AC: 122526 AN: 151036 Hom.: 50035 Cov.: 27 AF XY: 0.811 AC XY: 59716 AN XY: 73654

Gnomad4 AFR AF: 0.890

Gnomad4 AMR AF: 0.848

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.809

Gnomad4 SAS AF: 0.611

Gnomad4 FIN AF: 0.827

Gnomad4 NFE AF: 0.777

Gnomad4 OTH AF: 0.794

Alfa AF: 0.778 Hom.: 5229

Bravo AF: 0.818

Asia WGS AF: 0.748 AC: 2590 AN: 3462

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 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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	-0.53
CADD	Benign	19
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12379259; hg19: chr9-2622121; COSMIC: COSV66073714; COSMIC: COSV66073714;