9-2621798-C-T

Variant names:

• chr9-2621798-C-T
• rs867729388
• NM_003383.5:c.-392C>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.-392C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 484,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.190
• 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=-0.63).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000195 (65/333028) while in subpopulation MID AF = 0.00421 (6/1426). AF 95% confidence interval is 0.00183. There are 1 homozygotes in GnomAdExome4. There are 49 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. 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.-392C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_003374.3
	VLDLR	NM_003383.5	MANE Select	c.-392C>T		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-392C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001018066.1	P98155-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.-392C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.-392C>T		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+302G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151828 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000195 AC: 65 AN: 333028 Hom.: 1 Cov.: 0 AF XY: 0.000261 AC XY: 49 AN XY: 187720

African (AFR) AF: 0.000131 AC: 1 AN: 7656

American (AMR) AF: 0.000118 AC: 3 AN: 25460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12362

East Asian (EAS) AF: 0.00 AC: 0 AN: 9898

South Asian (SAS) AF: 0.000554 AC: 32 AN: 57728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16296

Middle Eastern (MID) AF: 0.00421 AC: 6 AN: 1426

European-Non Finnish (NFE) AF: 0.0000918 AC: 17 AN: 185148

Other (OTH) AF: 0.000352 AC: 6 AN: 17054

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151940 Hom.: 1 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74296

African (AFR) AF: 0.000169 AC: 7 AN: 41476

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000140

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	1	-	Congenital cerebellar hypoplasia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.19
PromoterAI		-0.026	Neutral

Splicing

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

Other links and lift over

dbSNP: rs867729388; hg19: chr9-2621798;