chr9-2622146-ACGG-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_003383.5(VLDLR):​c.-21_-19delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,374,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0028 (2 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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-ACGG-A is Benign according to our data. Variant chr9-2622146-ACGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366355.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00153 (230/150640) while in subpopulation AMR AF = 0.00289 (44/15202). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.-21_-19delGGC		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-21_-19delGGC		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-21_-19delGGC		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_-19delGGC		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.225_227delCCG		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.-21_-19delGGC		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 231 AN: 150530 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.0210

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00465 AC: 233 AN: 50120 AF XY: 0.00438

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00958

Gnomad FIN exome AF: 0.000452

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00277 AC: 3392 AN: 1223634 Hom.: 2 AF XY: 0.00274 AC XY: 1645 AN XY: 601320

African (AFR) AF: 0.00406 AC: 96 AN: 23640

American (AMR) AF: 0.00370 AC: 88 AN: 23752

Ashkenazi Jewish (ASJ) AF: 0.00412 AC: 82 AN: 19884

East Asian (EAS) AF: 0.00162 AC: 46 AN: 28368

South Asian (SAS) AF: 0.00131 AC: 83 AN: 63404

European-Finnish (FIN) AF: 0.000200 AC: 6 AN: 30016

Middle Eastern (MID) AF: 0.00559 AC: 28 AN: 5008

European-Non Finnish (NFE) AF: 0.00285 AC: 2792 AN: 978414

Other (OTH) AF: 0.00334 AC: 171 AN: 51148

GnomAD4 genome AF: 0.00153 AC: 230 AN: 150640 Hom.: 0 Cov.: 0 AF XY: 0.00150 AC XY: 110 AN XY: 73538

African (AFR) AF: 0.000292 AC: 12 AN: 41112

American (AMR) AF: 0.00289 AC: 44 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4972

South Asian (SAS) AF: 0.000629 AC: 3 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00209 AC: 141 AN: 67426

Other (OTH) AF: 0.00286 AC: 6 AN: 2098

Alfa AF: 0.00363 Hom.: 675

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
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: rs71329437; hg19: chr9-2622146; COSMIC: COSV107506815; COSMIC: COSV107506815;