Genetic Variant VLDLR-AS1:n.222_227delCCGCCG (chr9-2622146-ACGGCGG-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The ENST00000453601.5(VLDLR-AS1):n.222_227delCCGCCG 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 0.00125 in 1,392,208 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

VLDLR-AS1
ENST00000453601.5 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B: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 -6 ACMG points.

BP6

Variant 9-2622146-ACGGCGG-A is Benign according to our data. Variant chr9-2622146-ACGGCGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 420696.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5 link	c.-24_-19delGGCGGC		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.-24_-19delGGCGGC		5_prime_UTR_variant	Exon 1 of 19	1	NM_003383.5	ENSP00000371532.2		P98155-1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

239

AN:

150560

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00408

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000601

Gnomad SAS

AF:

0.00440

Gnomad FIN

AF:

0.000384

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.00160

AC:

AN:

50120

AF XY:

0.00171

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.00189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.000904

Gnomad NFE exome

AF:

0.000554

Gnomad OTH exome

AF:

0.00126

GnomAD4 exome

AF:

0.00120

AC:

1496

AN:

1241538

Hom.:

AF XY:

0.00133

AC XY:

814

AN XY:

610370

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

25700

American (AMR)

AF:

0.00207

AC:

AN:

24120

Ashkenazi Jewish (ASJ)

AF:

0.0000987

AC:

AN:

20256

East Asian (EAS)

AF:

0.000804

AC:

AN:

29844

South Asian (SAS)

AF:

0.00466

AC:

302

AN:

64822

European-Finnish (FIN)

AF:

0.000231

AC:

AN:

30350

Middle Eastern (MID)

AF:

0.00137

AC:

AN:

5100

European-Non Finnish (NFE)

AF:

0.00101

AC:

1004

AN:

989284

Other (OTH)

AF:

0.00123

AC:

AN:

52062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.00159

AC:

240

AN:

150670

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

107

AN XY:

73548

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41122

American (AMR)

AF:

0.00408

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3462

East Asian (EAS)

AF:

0.000603

AC:

AN:

4972

South Asian (SAS)

AF:

0.00440

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.000384

AC:

AN:

10408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

67432

Other (OTH)

AF:

0.00238

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000145

Hom.:

675

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 13, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Publications

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9-2622146-ACGGCGGCGGCGG-ACGGCGG

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