NM_003383.5:c.-113C>G

Variant names:

• chr9-2622077-C-G
• rs34433332
• NM_003383.5:c.-113C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003383.5(VLDLR):​c.-113C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,074,310 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 31)
  • Exomes 𝑓: 0.016 (211 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.268
• Publications: 2 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-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-2622077-C-G is Benign according to our data. Variant chr9-2622077-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366350.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1728/151894) while in subpopulation NFE AF = 0.0179 (1216/67874). AF 95% confidence interval is 0.0171. There are 13 homozygotes in GnomAd4. There are 795 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.-113C>G		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-113C>G		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-113C>G		5_prime_UTR	Exon 1 of 18	NP_001309154.1	A0A7P0T897

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.-113C>G		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+23G>C		intron	N/A
	VLDLR	ENST00000947327.1		c.-113C>G		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1729 AN: 151784 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0163 AC: 15019 AN: 922416 Hom.: 211 Cov.: 12 AF XY: 0.0160 AC XY: 7412 AN XY: 461994

African (AFR) AF: 0.00222 AC: 42 AN: 18956

American (AMR) AF: 0.00567 AC: 114 AN: 20096

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 244 AN: 16572

East Asian (EAS) AF: 0.0000373 AC: 1 AN: 26832

South Asian (SAS) AF: 0.0122 AC: 685 AN: 55954

European-Finnish (FIN) AF: 0.0185 AC: 540 AN: 29190

Middle Eastern (MID) AF: 0.00816 AC: 33 AN: 4044

European-Non Finnish (NFE) AF: 0.0179 AC: 12726 AN: 710092

Other (OTH) AF: 0.0156 AC: 634 AN: 40680

GnomAD4 genome AF: 0.0114 AC: 1728 AN: 151894 Hom.: 13 Cov.: 31 AF XY: 0.0107 AC XY: 795 AN XY: 74240

African (AFR) AF: 0.00263 AC: 109 AN: 41482

American (AMR) AF: 0.00621 AC: 95 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.0113 AC: 54 AN: 4798

European-Finnish (FIN) AF: 0.0172 AC: 182 AN: 10580

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0179 AC: 1216 AN: 67874

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00581 Hom.: 2

Bravo AF: 0.0106

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	1	-	Congenital cerebellar hypoplasia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		0.27
PromoterAI		0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

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: rs34433332; hg19: chr9-2622077;