9-2622146-ACGGCGG-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_003383.5(VLDLR):c.-24_-19del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,392,208 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.45

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 9-2622146-ACGGCGG-A is Benign according to our data. Variant chr9-2622146-ACGGCGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 420696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00159 (240/150670) while in subpopulation SAS AF= 0.0044 (21/4774). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.-24_-19del		5_prime_UTR_variant	1/19	ENST00000382100.8
VLDLR-AS1	NR_015375.2	n.222_227del		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.-24_-19del		5_prime_UTR_variant	1/19	1	NM_003383.5
VLDLR-AS1	ENST00000657742.1	n.222_227del		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 239 AN: 150560 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000601

Gnomad SAS AF: 0.00440

Gnomad FIN AF: 0.000384

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00160 AC: 80 AN: 50120 Hom.: 1 AF XY: 0.00171 AC XY: 48 AN XY: 28098

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00216

Gnomad SAS exome AF: 0.00373

Gnomad FIN exome AF: 0.000904

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00126

GnomAD4 exome AF: 0.00120 AC: 1496 AN: 1241538 Hom.: 6 AF XY: 0.00133 AC XY: 814 AN XY: 610370

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.0000987

Gnomad4 EAS exome AF: 0.000804

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.000231

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00159 AC: 240 AN: 150670 Hom.: 1 Cov.: 0 AF XY: 0.00145 AC XY: 107 AN XY: 73548

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00408

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000603

Gnomad4 SAS AF: 0.00440

Gnomad4 FIN AF: 0.000384

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00238

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2017

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71329437; hg19: chr9-2622146;