chr9-2644799-T-C

Variant names:

• chr9-2644799-T-C
• rs142885301
• NM_003383.5:c.1132T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. 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:4
• Conservation: PhyloP100: 5.96
• Publications: 6 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, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 281 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.1132T>C	p.Tyr378His	missense	Exon 8 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.1132T>C	p.Tyr378His	missense	Exon 8 of 18	NP_001018066.1
	VLDLR	NM_001322225.2		c.1009T>C	p.Tyr337His	missense	Exon 7 of 18	NP_001309154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.1132T>C	p.Tyr378His	missense	Exon 8 of 19	ENSP00000371532.2
	VLDLR	ENST00000382099.3	TSL:1	c.688T>C	p.Tyr230His	missense	Exon 4 of 15	ENSP00000371531.3
	VLDLR	ENST00000681306.1		c.1132T>C	p.Tyr378His	missense	Exon 8 of 18	ENSP00000506072.1

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

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251350 AF XY: 0.000221

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 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

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000487 AC: 542 AN: 1112008

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

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

African (AFR) AF: 0.000121 AC: 5 AN: 41468

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000343 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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Mar 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35668055)

Jan 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2

not specified Uncertain:1

Jun 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 17, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.81
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.96	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
Mutation Taster		=69/31	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: rs142885301; hg19: chr9-2644799;