NM_003383.5:c.-171G>C

Variant names:

• chr9-2622019-G-C
• rs35763266
• NM_003383.5:c.-171G>C

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.-171G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 656,412 control chromosomes in the GnomAD database, including 20 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 0.0058 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (16 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: -0.0510
• Publications: 1 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=-0.52).
• BP6: Variant 9-2622019-G-C is Benign according to our data. Variant chr9-2622019-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366347.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00577 (877/152054) while in subpopulation NFE AF = 0.0086 (584/67944). AF 95% confidence interval is 0.00802. There are 4 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.-171G>C		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-171G>C		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-171G>C		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.-171G>C		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+81C>G		intron	N/A
	VLDLR	ENST00000947327.1		c.-171G>C		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 878 AN: 151940 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00859

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00622 AC: 3139 AN: 504358 Hom.: 16 Cov.: 7 AF XY: 0.00600 AC XY: 1607 AN XY: 267614

African (AFR) AF: 0.000897 AC: 10 AN: 11144

American (AMR) AF: 0.00151 AC: 35 AN: 23238

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 17 AN: 14990

East Asian (EAS) AF: 0.00 AC: 0 AN: 25154

South Asian (SAS) AF: 0.00195 AC: 96 AN: 49114

European-Finnish (FIN) AF: 0.0112 AC: 342 AN: 30596

Middle Eastern (MID) AF: 0.00172 AC: 4 AN: 2332

European-Non Finnish (NFE) AF: 0.00777 AC: 2490 AN: 320426

Other (OTH) AF: 0.00530 AC: 145 AN: 27364

GnomAD4 genome AF: 0.00577 AC: 877 AN: 152054 Hom.: 4 Cov.: 31 AF XY: 0.00596 AC XY: 443 AN XY: 74334

African (AFR) AF: 0.00130 AC: 54 AN: 41500

American (AMR) AF: 0.00458 AC: 70 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00860 AC: 584 AN: 67944

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00309 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

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	-0.52
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		-0.051
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs35763266; hg19: chr9-2622019;