chr9-2643847-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003383.5(VLDLR):c.954C>T(p.Cys318Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,614,162 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 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 13 hom. )

Consequence

VLDLR
NM_003383.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0730

Publications

1 publications found

Variant links:

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

VLDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 9-2643847-C-T is Benign according to our data. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2643847-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 212566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.073 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000578 (88/152278) while in subpopulation SAS AF = 0.0102 (49/4820). AF 95% confidence interval is 0.0079. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5 link	c.954C>T	p.Cys318Cys	synonymous_variant	Exon 7 of 19	ENST00000382100.8	NP_003374.3	P98155-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8 link	c.954C>T	p.Cys318Cys	synonymous_variant	Exon 7 of 19	1	NM_003383.5	ENSP00000371532.2		P98155-1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00147

AC:

369

AN:

250910

AF XY:

0.00189

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000530

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00102

AC:

1492

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

912

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00927

AC:

800

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000521

AC:

579

AN:

1112008

Other (OTH)

AF:

0.00132

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000578

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0102

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68034

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000556

Hom.:

Bravo

AF:

0.000332

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VLDLR: BP4, BP7, BS2 -

Feb 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.6

(source)

DANN

Benign

0.49

PhyloP100

0.073

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over