9-2648747-C-T

Variant names:

• chr9-2648747-C-T
• rs79720897
• NM_003383.5:c.2041C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003383.5(VLDLR):​c.2041C>T​(p.Leu681Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0079 in 1,614,162 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L681L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (93 hom.)
• Consequence: VLDLR NM_003383.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.68
• Publications: 9 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 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 9-2648747-C-T is Benign according to our data. Variant chr9-2648747-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130706.
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00546 (831/152290) while in subpopulation SAS AF = 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 5 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2041C>T	p.Leu681Leu	synonymous	Exon 14 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.2041C>T	p.Leu681Leu	synonymous	Exon 14 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.1918C>T	p.Leu640Leu	synonymous	Exon 13 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.2041C>T	p.Leu681Leu	synonymous	Exon 14 of 19	ENSP00000371532.2	P98155-1
	VLDLR	ENST00000382099.3	TSL:1	c.1597C>T	p.Leu533Leu	synonymous	Exon 10 of 15	ENSP00000371531.3	A0A804CHQ2
	VLDLR	ENST00000947327.1		c.2038C>T	p.Leu680Leu	synonymous	Exon 14 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00693 AC: 1741 AN: 251352 AF XY: 0.00795

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00881

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00815 AC: 11921 AN: 1461872 Hom.: 93 Cov.: 32 AF XY: 0.00848 AC XY: 6164 AN XY: 727238

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0164 AC: 1415 AN: 86258

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53420

Middle Eastern (MID) AF: 0.0160 AC: 92 AN: 5766

European-Non Finnish (NFE) AF: 0.00860 AC: 9564 AN: 1111996

Other (OTH) AF: 0.00652 AC: 394 AN: 60396

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00530 AC XY: 395 AN XY: 74462

African (AFR) AF: 0.00113 AC: 47 AN: 41554

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4816

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00870 AC: 592 AN: 68028

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00706 Hom.: 5

Bravo AF: 0.00547

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.00948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	1	-	Congenital cerebellar hypoplasia (1)
-	-	1	VLDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	8.6
DANN	Benign	0.79
PhyloP100		2.7
Mutation Taster		=99/1	polymorphism

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: rs79720897; hg19: chr9-2648747;