chr1-25543763-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015627.3(LDLRAP1):​c.65G>T​(p.Trp22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,208,548 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W22R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

3
1
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.24

Publications

6 publications found
Variant links:
Genes affected
LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]
LDLRAP1 Gene-Disease associations (from GenCC):
  • hypercholesterolemia, familial, 4
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40298992).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRAP1NM_015627.3 linkc.65G>T p.Trp22Leu missense_variant Exon 1 of 9 ENST00000374338.5 NP_056442.2 Q5SW96B3KR97

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRAP1ENST00000374338.5 linkc.65G>T p.Trp22Leu missense_variant Exon 1 of 9 1 NM_015627.3 ENSP00000363458.4 Q5SW96
LDLRAP1ENST00000718277.1 linkc.65G>T p.Trp22Leu missense_variant Exon 1 of 10 ENSP00000520715.1
LDLRAP1ENST00000718287.1 linkc.65G>T p.Trp22Leu missense_variant Exon 1 of 6 ENSP00000520725.1
LDLRAP1ENST00000718288.1 linkn.65G>T non_coding_transcript_exon_variant Exon 1 of 10 ENSP00000520726.1

Frequencies

GnomAD3 genomes
AF:
0.0000330
AC:
5
AN:
151672
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
13
AN:
1056876
Hom.:
0
Cov.:
30
AF XY:
0.0000160
AC XY:
8
AN XY:
498900
show subpopulations
African (AFR)
AF:
0.0000455
AC:
1
AN:
22000
American (AMR)
AF:
0.000131
AC:
1
AN:
7620
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
13142
East Asian (EAS)
AF:
0.00
AC:
0
AN:
24532
South Asian (SAS)
AF:
0.00
AC:
0
AN:
19358
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
20662
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2854
European-Non Finnish (NFE)
AF:
0.0000111
AC:
10
AN:
904862
Other (OTH)
AF:
0.0000239
AC:
1
AN:
41846
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000330
AC:
5
AN:
151672
Hom.:
0
Cov.:
32
AF XY:
0.0000405
AC XY:
3
AN XY:
74100
show subpopulations
African (AFR)
AF:
0.0000967
AC:
4
AN:
41382
American (AMR)
AF:
0.0000657
AC:
1
AN:
15218
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10436
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67852
Other (OTH)
AF:
0.00
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.555
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4 Uncertain:3
Mar 18, 2022
New York Genome Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 08, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 22 of the LDLRAP1 protein (p.Trp22Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLRAP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 11, 2023
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Benign
0.93
DEOGEN2
Uncertain
0.73
D
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.80
T
M_CAP
Pathogenic
0.96
D
MetaRNN
Benign
0.40
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L
PhyloP100
3.2
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.1
D
REVEL
Benign
0.13
Sift
Benign
0.049
D
Sift4G
Benign
0.12
T
Polyphen
0.48
P
Vest4
0.33
MutPred
0.41
Loss of MoRF binding (P = 0.0567);
MVP
0.50
MPC
0.35
ClinPred
0.79
D
GERP RS
3.0
PromoterAI
0.048
Neutral
Varity_R
0.40
gMVP
0.38
Mutation Taster
=33/67
disease causing

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

Other links and lift over

dbSNP: rs121908324; hg19: chr1-25870254; API