rs142885301

chr9-2644799-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_003383.5(VLDLR):c.1132T>C(p.Tyr378His) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y378Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.96

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000393 (574/1461882) while in subpopulation NFE AF= 0.000487 (542/1112008). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4_exome. There are 281 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VLDLR	NM_003383.5	c.1132T>C	p.Tyr378His	missense_variant	8/19	ENST00000382100.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VLDLR	ENST00000382100.8	c.1132T>C	p.Tyr378His	missense_variant	8/19	1	NM_003383.5

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251350 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135870

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000386 AC XY: 281 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74356

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000351 Hom.: 1

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 04, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.11	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.96	D;D
Vest4		0.46
MVP		0.89
MPC		0.55
ClinPred		0.23	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs142885301; hg19: chr9-2644799;