rs140526335

chr9-2639898-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003383.5(VLDLR):c.242A>G(p.Asn81Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,614,184 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.49

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-2639898-A-G is Benign according to our data. Variant chr9-2639898-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 431884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2639898-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00133 (203/152298) while in subpopulation SAS AF= 0.00746 (36/4828). AF 95% confidence interval is 0.00554. There are 2 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.242A>G	p.Asn81Ser	missense_variant	3/19	ENST00000382100.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.242A>G	p.Asn81Ser	missense_variant	3/19	1	NM_003383.5

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00197 AC: 495 AN: 251488 Hom.: 2 AF XY: 0.00215 AC XY: 292 AN XY: 135916

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00699

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00175 AC: 2563 AN: 1461886 Hom.: 11 Cov.: 31 AF XY: 0.00189 AC XY: 1378 AN XY: 727242

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00721

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74468

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00155 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	This variant is associated with the following publications: (PMID: 24036952) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	VLDLR: BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 08, 2017	- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Benign	0.0041
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.39	N;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.024	B;.;B
Vest4		0.19
MVP		0.78
MPC		0.098
ClinPred		0.044	T
GERP RS		5.9
Varity_R		0.053
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs140526335; hg19: chr9-2639898;