chr9-2622146-A-ACGGCGG

Variant names:

• chr9-2622146-A-ACGGCGG
• rs71329437
• NM_003383.5:c.-24_-19dupGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_003383.5(VLDLR):​c.-24_-19dupGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000637 (96/150670) while in subpopulation EAS AF = 0.00724 (36/4970). AF 95% confidence interval is 0.00538. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-24_-19dupGGCGGC		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-24_-19dupGGCGGC		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-24_-19dupGGCGGC		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.-24_-19dupGGCGGC		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.222_227dupCCGCCG		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.-24_-19dupGGCGGC		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 97 AN: 150560 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00742

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000534

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00102 AC: 51 AN: 50120 AF XY: 0.000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.00803

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000689 AC: 856 AN: 1241622 Hom.: 1 Cov.: 0 AF XY: 0.000695 AC XY: 424 AN XY: 610426

African (AFR) AF: 0.000311 AC: 8 AN: 25712

American (AMR) AF: 0.000995 AC: 24 AN: 24122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20260

East Asian (EAS) AF: 0.00767 AC: 229 AN: 29846

South Asian (SAS) AF: 0.00139 AC: 90 AN: 64836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30350

Middle Eastern (MID) AF: 0.00314 AC: 16 AN: 5100

European-Non Finnish (NFE) AF: 0.000455 AC: 450 AN: 989326

Other (OTH) AF: 0.000749 AC: 39 AN: 52070

GnomAD4 genome AF: 0.000637 AC: 96 AN: 150670 Hom.: 0 Cov.: 0 AF XY: 0.000680 AC XY: 50 AN XY: 73548

African (AFR) AF: 0.000170 AC: 7 AN: 41122

American (AMR) AF: 0.000592 AC: 9 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00724 AC: 36 AN: 4970

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10410

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000534 AC: 36 AN: 67432

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.000508 Hom.: 675

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=298/2	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs71329437; hg19: chr9-2622146;