Genetic Variant LDLRAD3:p.Ser69Leu (chr11-36081665-C-T) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

LDLRAD3 links:

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
LDLRAD3	NM_174902.4 link	c.206C>T	p.Ser69Leu	missense_variant	Exon 3 of 6	ENST00000315571.6	NP_777562.1	Q86YD5-1
LDLRAD3	NM_001304264.2 link	c.-274C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6		NP_001291193.1	Q86YD5
LDLRAD3	NM_001304263.2 link	c.59C>T	p.Ser20Leu	missense_variant	Exon 2 of 5		NP_001291192.1	Q86YD5-2
LDLRAD3	NM_001304264.2 link	c.-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	UniProt
LDLRAD3	ENST00000315571.6 link	c.206C>T	p.Ser69Leu	missense_variant	Exon 3 of 6	1	NM_174902.4	ENSP00000318607.5	Q86YD5-1
LDLRAD3	ENST00000528989.5 link	c.59C>T	p.Ser20Leu	missense_variant	Exon 2 of 5	1		ENSP00000433954.1	Q86YD5-2
LDLRAD3	ENST00000524419.5 link	c.59C>T	p.Ser20Leu	missense_variant	Exon 2 of 6	5		ENSP00000434313.1	E9PR86
LDLRAD3	ENST00000532490.1 link	n.160C>T		non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

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:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

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:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

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.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

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

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;T;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.96

.;.;L

PrimateAI

Uncertain

0.78

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over