rs3780181

Variant names:

• chr9-2640759-A-G
• rs3780181
• NM_003383.5:c.326-618A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003383.5(VLDLR):​c.326-618A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,198 control chromosomes in the GnomAD database, including 1,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (1279 hom., cov: 32)
• Consequence: VLDLR NM_003383.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.657
• Publications: 65 publications found

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 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), G2P, PanelApp Australia
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-2640759-A-G is Benign according to our data. Variant chr9-2640759-A-G is described in ClinVar as Benign. ClinVar VariationId is 1181633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.326-618A>G		intron	N/A	NP_003374.3
	VLDLR	NM_001018056.3		c.326-618A>G		intron	N/A	NP_001018066.1
	VLDLR	NM_001322225.2		c.325+778A>G		intron	N/A	NP_001309154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.326-618A>G		intron	N/A	ENSP00000371532.2
	VLDLR	ENST00000947327.1		c.326-618A>G		intron	N/A	ENSP00000617386.1
	VLDLR	ENST00000916502.1		c.326-618A>G		intron	N/A	ENSP00000586561.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17157 AN: 152080 Hom.: 1278 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.113 AC: 17177 AN: 152198 Hom.: 1279 Cov.: 32 AF XY: 0.111 AC XY: 8272 AN XY: 74426

African (AFR) AF: 0.211 AC: 8739 AN: 41500

American (AMR) AF: 0.113 AC: 1730 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3470

East Asian (EAS) AF: 0.103 AC: 535 AN: 5172

South Asian (SAS) AF: 0.0592 AC: 286 AN: 4830

European-Finnish (FIN) AF: 0.0473 AC: 502 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4714 AN: 68004

Other (OTH) AF: 0.104 AC: 220 AN: 2114

Alfa AF: 0.0836 Hom.: 2360

Bravo AF: 0.121

Asia WGS AF: 0.0980 AC: 342 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.73
DANN	Benign	0.73
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3780181; hg19: chr9-2640759;