chr9-2622068-T-C

Variant names:

• chr9-2622068-T-C
• rs886063802
• NM_003383.5:c.-122T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003383.5(VLDLR):​c.-122T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 129,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.130
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000388 (50/129022) while in subpopulation AFR AF = 0.00132 (47/35550). AF 95% confidence interval is 0.00102. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-122T>C		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-122T>C		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-122T>C		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.-122T>C		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+32A>G		intron	N/A
	VLDLR	ENST00000947327.1		c.-122T>C		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 50 AN: 128996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000345

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000687 AC: 38 AN: 552896 Hom.: 0 Cov.: 10 AF XY: 0.0000783 AC XY: 22 AN XY: 281080

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000332 AC: 4 AN: 12044

American (AMR) AF: 0.0000746 AC: 1 AN: 13406

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 3 AN: 10886

East Asian (EAS) AF: 0.00 AC: 0 AN: 17146

South Asian (SAS) AF: 0.000202 AC: 9 AN: 44446

European-Finnish (FIN) AF: 0.000358 AC: 7 AN: 19540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2828

European-Non Finnish (NFE) AF: 0.0000270 AC: 11 AN: 407588

Other (OTH) AF: 0.000120 AC: 3 AN: 25012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000388 AC: 50 AN: 129022 Hom.: 0 Cov.: 31 AF XY: 0.000475 AC XY: 30 AN XY: 63218

African (AFR) AF: 0.00132 AC: 47 AN: 35550

American (AMR) AF: 0.00 AC: 0 AN: 12696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3130

East Asian (EAS) AF: 0.00 AC: 0 AN: 4308

South Asian (SAS) AF: 0.00 AC: 0 AN: 4292

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000345 AC: 2 AN: 57952

Other (OTH) AF: 0.00 AC: 0 AN: 1706

Alfa AF: 0.00691 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	1	-	Congenital cerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		-0.13
PromoterAI		-0.040	Neutral

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: rs886063802; hg19: chr9-2622068;