rs530164662

Variant names:

• chr9-2621560-A-G
• rs530164662
• ENST00000453601.5:n.274+540T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000453601.5(VLDLR-AS1):​n.274+540T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 394,298 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (19 hom.)
• Consequence: VLDLR-AS1 ENST00000453601.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

Genes affected

VLDLR-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

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 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-2621560-A-G is Benign according to our data. Variant chr9-2621560-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1201496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00516 (1250/242242) while in subpopulation EAS AF = 0.0338 (749/22160). AF 95% confidence interval is 0.0318. There are 19 homozygotes in GnomAdExome4. There are 589 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453601.5. 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-AS1	NR_015375.2		n.274+540T>C		intron	N/A
	VLDLR	NM_003383.5	MANE Select	c.-630A>G		upstream_gene	N/A	NP_003374.3
	VLDLR	NM_001018056.3		c.-630A>G		upstream_gene	N/A	NP_001018066.1	P98155-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.274+540T>C		intron	N/A
	VLDLR	ENST00000382096.6	TSL:5	c.-71+257A>G		intron	N/A	ENSP00000371528.2	Q5VVF8
	VLDLR-AS1	ENST00000657742.1		n.274+540T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 326 AN: 151948 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00516 AC: 1250 AN: 242242 Hom.: 19 AF XY: 0.00478 AC XY: 589 AN XY: 123220

African (AFR) AF: 0.000297 AC: 2 AN: 6736

American (AMR) AF: 0.00241 AC: 17 AN: 7046

Ashkenazi Jewish (ASJ) AF: 0.00250 AC: 22 AN: 8816

East Asian (EAS) AF: 0.0338 AC: 749 AN: 22160

South Asian (SAS) AF: 0.00107 AC: 3 AN: 2796

European-Finnish (FIN) AF: 0.0157 AC: 324 AN: 20654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1256

European-Non Finnish (NFE) AF: 0.000625 AC: 98 AN: 156812

Other (OTH) AF: 0.00219 AC: 35 AN: 15966

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152056 Hom.: 3 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41528

American (AMR) AF: 0.00131 AC: 20 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3464

East Asian (EAS) AF: 0.0111 AC: 57 AN: 5134

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0172 AC: 182 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67942

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.000956

Asia WGS AF: 0.00783 AC: 27 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.46
PhyloP100		1.8
PromoterAI		-0.038	Neutral

Splicing

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

Other links and lift over

dbSNP: rs530164662; hg19: chr9-2621560;