9-2622069-C-T

Variant names:

• chr9-2622069-C-T
• rs886063803
• NM_003383.5:c.-121C>T

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.-121C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 965,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.126
• 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=-0.65).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00016 (130/814108) while in subpopulation EAS AF = 0.00487 (125/25652). AF 95% confidence interval is 0.00418. There are 1 homozygotes in GnomAdExome4. There are 67 alleles in the male GnomAdExome4 subpopulation. Median coverage is 11. 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.-121C>T		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-121C>T		5_prime_UTR	Exon 1 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.-121C>T		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.-121C>T		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+31G>A		intron	N/A
	VLDLR	ENST00000947327.1		c.-121C>T		5_prime_UTR	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151750 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000979

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 130 AN: 814108 Hom.: 1 Cov.: 11 AF XY: 0.000163 AC XY: 67 AN XY: 411026

African (AFR) AF: 0.00 AC: 0 AN: 16726

American (AMR) AF: 0.00 AC: 0 AN: 19376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15610

East Asian (EAS) AF: 0.00487 AC: 125 AN: 25652

South Asian (SAS) AF: 0.00 AC: 0 AN: 53468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3672

European-Non Finnish (NFE) AF: 0.00000489 AC: 3 AN: 614122

Other (OTH) AF: 0.0000540 AC: 2 AN: 37022

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151858 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000982 AC: 5 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

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	-0.65
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		0.13
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs886063803; hg19: chr9-2622069;