chr11-36081665-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001304264.2(LDLRAD3):​c.-274C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

LDLRAD3
NM_001304264.2 5_prime_UTR_premature_start_codon_gain

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.50
Variant links:
Genes affected
LDLRAD3 (HGNC:27046): (low density lipoprotein receptor class A domain containing 3) Predicted to enable amyloid-beta binding activity. Predicted to act upstream of or within receptor-mediated endocytosis and regulation of protein processing. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRAD3NM_174902.4 linkc.206C>T p.Ser69Leu missense_variant Exon 3 of 6 ENST00000315571.6 NP_777562.1 Q86YD5-1
LDLRAD3NM_001304264.2 linkc.-274C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 2 of 6 NP_001291193.1 Q86YD5
LDLRAD3NM_001304263.2 linkc.59C>T p.Ser20Leu missense_variant Exon 2 of 5 NP_001291192.1 Q86YD5-2
LDLRAD3NM_001304264.2 linkc.-274C>T 5_prime_UTR_variant Exon 2 of 6 NP_001291193.1 Q86YD5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRAD3ENST00000315571.6 linkc.206C>T p.Ser69Leu missense_variant Exon 3 of 6 1 NM_174902.4 ENSP00000318607.5 Q86YD5-1
LDLRAD3ENST00000528989.5 linkc.59C>T p.Ser20Leu missense_variant Exon 2 of 5 1 ENSP00000433954.1 Q86YD5-2
LDLRAD3ENST00000524419.5 linkc.59C>T p.Ser20Leu missense_variant Exon 2 of 6 5 ENSP00000434313.1 E9PR86
LDLRAD3ENST00000532490.1 linkn.160C>T non_coding_transcript_exon_variant Exon 3 of 5 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000576
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251476
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.0000358
AC XY:
26
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00103
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152352
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.206C>T (p.S69L) alteration is located in exon 3 (coding exon 3) of the LDLRAD3 gene. This alteration results from a C to T substitution at nucleotide position 206, causing the serine (S) at amino acid position 69 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;.;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;T;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Uncertain
0.73
D;D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Benign
0.96
.;.;L
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0060
D;D;D
Sift4G
Uncertain
0.017
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.84
MVP
0.88
MPC
0.62
ClinPred
0.74
D
GERP RS
6.0
Varity_R
0.28
gMVP
0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144306758; hg19: chr11-36103215; COSMIC: COSV59682709; API