9-2621482-C-G

Variant names:

• chr9-2621482-C-G
• rs7852409
• ENST00000453601.5:n.274+618G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000453601.5(VLDLR-AS1):​n.274+618G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 398,658 control chromosomes in the GnomAD database, including 106,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36009 hom., cov: 33)
  • Exomes 𝑓: 0.75 (69995 hom.)
• Consequence: VLDLR-AS1 ENST00000453601.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0700
• Publications: 8 publications found

Genes affected

VLDLR-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

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 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 9-2621482-C-G is Benign according to our data. Variant chr9-2621482-C-G is described in ClinVar as Benign. ClinVar VariationId is 667580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453601.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR-AS1	NR_015375.2		n.274+618G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+618G>C		intron	N/A
	VLDLR	ENST00000382096.6	TSL:5	c.-71+179C>G		intron	N/A	ENSP00000371528.2	Q5VVF8
	VLDLR-AS1	ENST00000657742.1		n.274+618G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102868 AN: 151938 Hom.: 35998 Cov.: 33

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.695

GnomAD4 exome AF: 0.752 AC: 185421 AN: 246606 Hom.: 69995 AF XY: 0.754 AC XY: 94505 AN XY: 125310

African (AFR) AF: 0.513 AC: 3599 AN: 7014

American (AMR) AF: 0.653 AC: 4796 AN: 7342

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 6830 AN: 9152

East Asian (EAS) AF: 0.829 AC: 18912 AN: 22826

South Asian (SAS) AF: 0.745 AC: 1929 AN: 2588

European-Finnish (FIN) AF: 0.722 AC: 14921 AN: 20666

Middle Eastern (MID) AF: 0.738 AC: 964 AN: 1306

European-Non Finnish (NFE) AF: 0.762 AC: 121449 AN: 159358

Other (OTH) AF: 0.735 AC: 12021 AN: 16354

GnomAD4 genome AF: 0.677 AC: 102923 AN: 152052 Hom.: 36009 Cov.: 33 AF XY: 0.678 AC XY: 50381 AN XY: 74328

African (AFR) AF: 0.498 AC: 20645 AN: 41486

American (AMR) AF: 0.669 AC: 10216 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2529 AN: 3470

East Asian (EAS) AF: 0.840 AC: 4312 AN: 5136

South Asian (SAS) AF: 0.753 AC: 3626 AN: 4818

European-Finnish (FIN) AF: 0.709 AC: 7515 AN: 10594

Middle Eastern (MID) AF: 0.757 AC: 221 AN: 292

European-Non Finnish (NFE) AF: 0.762 AC: 51759 AN: 67962

Other (OTH) AF: 0.700 AC: 1477 AN: 2110

Alfa AF: 0.621 Hom.: 1942

Bravo AF: 0.665

Asia WGS AF: 0.776 AC: 2697 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		-0.070
PromoterAI		-0.068	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7852409; hg19: chr9-2621482;