chr9-2621884-T-TCCCTCCTCTCCCCTTGCCTC

Position:

• chr9-2621884-T-TCCCTCCTCTCCCCTTGCCTC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_003383.5(VLDLR):​c.-296_-277dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 597,922 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (12 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.211

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 -10 ACMG points.

• BP6: Variant 9-2621884-T-TCCCTCCTCTCCCCTTGCCTC is Benign according to our data. Variant chr9-2621884-T-TCCCTCCTCTCCCCTTGCCTC is described in ClinVar as [Likely_benign]. Clinvar id is 2659036.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000574 (87/151626) while in subpopulation SAS AF= 0.00733 (35/4776). AF 95% confidence interval is 0.00542. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-296_-277dup		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.274+215_274+216insGAGGCAAGGGGAGAGGAGGG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-296_-277dup		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.274+215_274+216insGAGGCAAGGGGAGAGGAGGG		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000581 AC: 88 AN: 151514 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00732

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000531

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00170 AC: 218 AN: 128164 Hom.: 3 AF XY: 0.00215 AC XY: 151 AN XY: 70148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000690

Gnomad ASJ exome AF: 0.000373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00820

Gnomad FIN exome AF: 0.000184

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00168 AC: 750 AN: 446296 Hom.: 12 Cov.: 0 AF XY: 0.00224 AC XY: 550 AN XY: 245114

Gnomad4 AFR exome AF: 0.0000791

Gnomad4 AMR exome AF: 0.000612

Gnomad4 ASJ exome AF: 0.000245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00947

Gnomad4 FIN exome AF: 0.0000818

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.000574 AC: 87 AN: 151626 Hom.: 0 Cov.: 31 AF XY: 0.000715 AC XY: 53 AN XY: 74140

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00733

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.000531

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000474 Hom.: 0

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

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

VLDLR: BS2; VLDLR-AS1: BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs539873248; hg19: chr9-2621884;