9-2621564-G-A

Position:

• chr9-2621564-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000382096.6(VLDLR):​c.-71+261G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0094 in 152,132 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 Likely benign (★).

• Frequency: Genomes: 𝑓 0.0094 (20 hom., cov: 32)
• Consequence: VLDLR ENST00000382096.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49

Genes affected

VLDLR-AS1 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-2621564-G-A is Benign according to our data. Variant chr9-2621564-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 673304.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0094 (1430/152132) while in subpopulation NFE AF= 0.0149 (1014/67958). AF 95% confidence interval is 0.0142. There are 20 homozygotes in gnomad4. There are 696 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VLDLR-AS1	NR_015375.2	n.274+536C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VLDLR-AS1	ENST00000453601.5	n.274+536C>T		intron_variant		1
VLDLR	ENST00000382096.6	c.-71+261G>A		intron_variant		5		ENSP00000371528.2
VLDLR-AS1	ENST00000657742.1	n.274+536C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1430 AN: 152026 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0115

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00940 AC: 1430 AN: 152132 Hom.: 20 Cov.: 32 AF XY: 0.00936 AC XY: 696 AN XY: 74392

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00945

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0117 Hom.: 3

Bravo AF: 0.00963

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142199771; hg19: chr9-2621564;