Genetic Variant VLDLR-AS1:n.225_227delCCG (chr9-2622146-ACGG-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000453601.5(VLDLR-AS1):n.225_227delCCG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,374,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0028 ( 2 hom. )

Consequence

VLDLR-AS1
ENST00000453601.5 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.45

Publications

3 publications found

Variant links:

Genes affected

VLDLR-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

VLDLR-AS1 links:

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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 9-2622146-ACGG-A is Benign according to our data. Variant chr9-2622146-ACGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366355.

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5 link	c.-21_-19delGGC		5_prime_UTR_variant	Exon 1 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.-21_-19delGGC		5_prime_UTR_variant	Exon 1 of 19	1	NM_003383.5	ENSP00000371532.2		P98155-1

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

231

AN:

150530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.0210

Gnomad AMR

AF:

0.00296

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000628

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00289

GnomAD2 exomes

AF:

0.00465

AC:

233

AN:

50120

AF XY:

0.00438

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.00407

Gnomad ASJ exome

AF:

0.00645

Gnomad EAS exome

AF:

0.00958

Gnomad FIN exome

AF:

0.000452

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00277

AC:

3392

AN:

1223634

Hom.:

AF XY:

0.00274

AC XY:

1645

AN XY:

601320

show subpopulations

African (AFR)

AF:

0.00406

AC:

AN:

23640

American (AMR)

AF:

0.00370

AC:

AN:

23752

Ashkenazi Jewish (ASJ)

AF:

0.00412

AC:

AN:

19884

East Asian (EAS)

AF:

0.00162

AC:

AN:

28368

South Asian (SAS)

AF:

0.00131

AC:

AN:

63404

European-Finnish (FIN)

AF:

0.000200

AC:

AN:

30016

Middle Eastern (MID)

AF:

0.00559

AC:

AN:

5008

European-Non Finnish (NFE)

AF:

0.00285

AC:

2792

AN:

978414

Other (OTH)

AF:

0.00334

AC:

171

AN:

51148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00153

AC:

230

AN:

150640

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

110

AN XY:

73538

show subpopulations

African (AFR)

AF:

0.000292

AC:

AN:

41112

American (AMR)

AF:

0.00289

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4972

South Asian (SAS)

AF:

0.000629

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00209

AC:

141

AN:

67426

Other (OTH)

AF:

0.00286

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00363

Hom.:

675

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital cerebellar hypoplasia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=300/0

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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9-2622146-ACGGCGGCGGCGG-ACGGCGGCGG

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