chr9-2622131-TGTC-T

Variant names:

• chr9-2622131-TGTC-T
• rs886063804
• NM_003383.5:c.-56_-54delCGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_003383.5(VLDLR):​c.-56_-54delCGT variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00021 in 1,429,164 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 0 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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000201 (261/1299656) while in subpopulation EAS AF = 0.000607 (19/31308). AF 95% confidence interval is 0.000397. There are 2 homozygotes in GnomAdExome4. There are 130 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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.-56_-54delCGT		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-56_-54delCGT		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-56_-54delCGT		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.-56_-54delCGT		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.240_242delGAC		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.-56_-54delCGT		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 37 AN: 129418 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000512

Gnomad FIN AF: 0.000121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 261 AN: 1299656 Hom.: 2 AF XY: 0.000203 AC XY: 130 AN XY: 639914

African (AFR) AF: 0.000406 AC: 11 AN: 27112

American (AMR) AF: 0.000222 AC: 6 AN: 27020

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 77 AN: 21816

East Asian (EAS) AF: 0.000607 AC: 19 AN: 31308

South Asian (SAS) AF: 0.0000711 AC: 5 AN: 70298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5294

European-Non Finnish (NFE) AF: 0.000115 AC: 118 AN: 1030448

Other (OTH) AF: 0.000459 AC: 25 AN: 54432

GnomAD4 genome AF: 0.000301 AC: 39 AN: 129508 Hom.: 0 Cov.: 30 AF XY: 0.000316 AC XY: 20 AN XY: 63318

African (AFR) AF: 0.000229 AC: 9 AN: 39318

American (AMR) AF: 0.00 AC: 0 AN: 12370

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 18 AN: 3094

East Asian (EAS) AF: 0.00 AC: 0 AN: 4356

South Asian (SAS) AF: 0.000512 AC: 2 AN: 3906

European-Finnish (FIN) AF: 0.000121 AC: 1 AN: 8262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000162 AC: 9 AN: 55460

Other (OTH) AF: 0.00 AC: 0 AN: 1752

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000230

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital cerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

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: rs886063804; hg19: chr9-2622131;