9-2622131-TGTC-T

Position:

• chr9-2622131-TGTC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003383.5(VLDLR):​c.-56_-54del variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00021 in 1,429,164 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000201 (261/1299656) while in subpopulation EAS AF= 0.000607 (19/31308). AF 95% confidence interval is 0.000397. There are 2 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.-56_-54del		5_prime_UTR_variant	1/19	ENST00000382100.8	NP_003374.3
VLDLR-AS1	NR_015375.2	n.240_242del		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.-56_-54del		5_prime_UTR_variant	1/19	1	NM_003383.5	ENSP00000371532
VLDLR-AS1	ENST00000657742.1	n.240_242del		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 37 AN: 129418 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000512

Gnomad FIN AF: 0.000121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 261 AN: 1299656 Hom.: 2 AF XY: 0.000203 AC XY: 130 AN XY: 639914

Gnomad4 AFR exome AF: 0.000406

Gnomad4 AMR exome AF: 0.000222

Gnomad4 ASJ exome AF: 0.00353

Gnomad4 EAS exome AF: 0.000607

Gnomad4 SAS exome AF: 0.0000711

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.000459

GnomAD4 genome AF: 0.000301 AC: 39 AN: 129508 Hom.: 0 Cov.: 30 AF XY: 0.000316 AC XY: 20 AN XY: 63318

Gnomad4 AFR AF: 0.000229

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00582

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000512

Gnomad4 FIN AF: 0.000121

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000230

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital cerebellar hypoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs886063804; hg19: chr9-2622131;