9-2622146-ACGGCGGCGGCGG-ACGG

Variant names:

• chr9-2622146-ACGGCGGCGG-A
• rs71329437
• NM_003383.5:c.-27_-19delGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_003383.5(VLDLR):​c.-27_-19delGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,386,978 control chromosomes in the GnomAD database, including 94,983 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.33 (8761 hom., cov: 0)
  • Exomes 𝑓: 0.38 (86222 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.45
• Publications: 3 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 -9 ACMG points.

• BP6: Variant 9-2622146-ACGGCGGCGG-A is Benign according to our data. Variant chr9-2622146-ACGGCGGCGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290493.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.-27_-19delGGCGGCGGC		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-27_-19delGGCGGCGGC		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-27_-19delGGCGGCGGC		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.-27_-19delGGCGGCGGC		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.219_227delCCGCCGCCG		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.-27_-19delGGCGGCGGC		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49501 AN: 150360 Hom.: 8751 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.302 AC: 15135 AN: 50120 AF XY: 0.293

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.380 AC: 469971 AN: 1236508 Hom.: 86222 AF XY: 0.375 AC XY: 227489 AN XY: 606996

African (AFR) AF: 0.194 AC: 4989 AN: 25658

American (AMR) AF: 0.397 AC: 9447 AN: 23794

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 6016 AN: 20152

East Asian (EAS) AF: 0.414 AC: 12290 AN: 29714

South Asian (SAS) AF: 0.235 AC: 15153 AN: 64504

European-Finnish (FIN) AF: 0.383 AC: 11574 AN: 30240

Middle Eastern (MID) AF: 0.281 AC: 1427 AN: 5078

European-Non Finnish (NFE) AF: 0.396 AC: 390612 AN: 985518

Other (OTH) AF: 0.356 AC: 18463 AN: 51850

GnomAD4 genome AF: 0.329 AC: 49548 AN: 150470 Hom.: 8761 Cov.: 0 AF XY: 0.330 AC XY: 24225 AN XY: 73448

African (AFR) AF: 0.198 AC: 8132 AN: 41054

American (AMR) AF: 0.414 AC: 6289 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1031 AN: 3460

East Asian (EAS) AF: 0.420 AC: 2085 AN: 4962

South Asian (SAS) AF: 0.238 AC: 1136 AN: 4764

European-Finnish (FIN) AF: 0.360 AC: 3734 AN: 10386

Middle Eastern (MID) AF: 0.348 AC: 101 AN: 290

European-Non Finnish (NFE) AF: 0.388 AC: 26168 AN: 67366

Other (OTH) AF: 0.333 AC: 699 AN: 2096

Alfa AF: 0.260 Hom.: 675

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Congenital cerebellar hypoplasia (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs71329437; hg19: chr9-2622146; COSMIC: COSV105314195; COSMIC: COSV105314195;