9-2622253-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_003383.5(VLDLR):c.64A>T(p.Ser22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,491,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

VLDLR
NM_003383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.84

Publications

0 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 links:

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

VLDLR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1477254).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000575 (77/1339884) while in subpopulation SAS AF = 0.000799 (59/73822). AF 95% confidence interval is 0.000635. There are 1 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VLDLR	NM_003383.5	MANE Select	c.64A>T	p.Ser22Cys	missense	Exon 1 of 19	NP_003374.3
VLDLR	NM_001018056.3		c.64A>T	p.Ser22Cys	missense	Exon 1 of 18	NP_001018066.1
VLDLR	NM_001322225.2		c.64A>T	p.Ser22Cys	missense	Exon 1 of 18	NP_001309154.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.64A>T	p.Ser22Cys	missense	Exon 1 of 19	ENSP00000371532.2
VLDLR-AS1	ENST00000453601.5	TSL:1	n.121T>A		non_coding_transcript_exon	Exon 1 of 4
VLDLR	ENST00000681306.1		c.64A>T	p.Ser22Cys	missense	Exon 1 of 18	ENSP00000506072.1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000164

AC:

AN:

91490

AF XY:

0.000271

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000364

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1339884

Hom.:

Cov.:

AF XY:

0.0000788

AC XY:

AN XY:

660288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27438

American (AMR)

AF:

0.00

AC:

AN:

30900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23654

East Asian (EAS)

AF:

0.00

AC:

AN:

30860

South Asian (SAS)

AF:

0.000799

AC:

AN:

73822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33088

Middle Eastern (MID)

AF:

0.000209

AC:

AN:

4790

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

1059336

Other (OTH)

AF:

0.0000357

AC:

AN:

55996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41340

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000469

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000780

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 21, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64A>T (p.S22C) alteration is located in exon 1 (coding exon 1) of the VLDLR gene. This alteration results from a A to T substitution at nucleotide position 64, causing the serine (S) at amino acid position 22 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.28

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.62

REVEL

Uncertain

0.30

Sift

Benign

0.079

Sift4G

Benign

0.062

Polyphen

0.80

Vest4

0.16

MutPred

0.49

Loss of disorder (P = 0.0048)

MVP

0.77

MPC

0.13

ClinPred

0.12

GERP RS

1.8

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.10

gMVP

0.35

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over