NM_003383.5:c.-21_-19dupGGC

Variant names:

• chr9-2622146-A-ACGG
• rs71329437
• NM_003383.5:c.-21_-19dupGGC

Variant summary

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

The NM_003383.5(VLDLR):​c.-21_-19dupGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5849 hom., cov: 0)
  • Exomes 𝑓: 0.29 (37238 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.20
• 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-A-ACGG is Benign according to our data. Variant chr9-2622146-A-ACGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287823.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 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.-21_-19dupGGC		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-21_-19dupGGC		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-21_-19dupGGC		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.-21_-19dupGGC		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.225_227dupCCG		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.-21_-19dupGGC		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38285 AN: 150414 Hom.: 5843 Cov.: 0

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.0532

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.302 AC: 15122 AN: 50120 AF XY: 0.309

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.0615

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.293 AC: 361375 AN: 1234812 Hom.: 37238 Cov.: 0 AF XY: 0.296 AC XY: 179468 AN XY: 607236

African (AFR) AF: 0.0877 AC: 2252 AN: 25664

American (AMR) AF: 0.248 AC: 5958 AN: 24044

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 6625 AN: 20164

East Asian (EAS) AF: 0.0443 AC: 1321 AN: 29818

South Asian (SAS) AF: 0.342 AC: 22102 AN: 64656

European-Finnish (FIN) AF: 0.346 AC: 10491 AN: 30318

Middle Eastern (MID) AF: 0.252 AC: 1285 AN: 5096

European-Non Finnish (NFE) AF: 0.302 AC: 296857 AN: 983234

Other (OTH) AF: 0.280 AC: 14484 AN: 51818

GnomAD4 genome AF: 0.254 AC: 38305 AN: 150524 Hom.: 5849 Cov.: 0 AF XY: 0.256 AC XY: 18827 AN XY: 73460

African (AFR) AF: 0.0964 AC: 3960 AN: 41092

American (AMR) AF: 0.242 AC: 3683 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1274 AN: 3460

East Asian (EAS) AF: 0.0533 AC: 265 AN: 4968

South Asian (SAS) AF: 0.366 AC: 1745 AN: 4762

European-Finnish (FIN) AF: 0.391 AC: 4059 AN: 10382

Middle Eastern (MID) AF: 0.234 AC: 68 AN: 290

European-Non Finnish (NFE) AF: 0.330 AC: 22205 AN: 67370

Other (OTH) AF: 0.256 AC: 538 AN: 2098

Alfa AF: 0.265 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)
-	1	1	not specified (2)
-	-	1	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
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: COSV66073212; COSMIC: COSV66073212;