11-36036240-A-G

Variant names:

• chr11-36036240-A-G
• rs765495963
• NM_174902.4:c.184A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_174902.4(LDLRAD3):​c.184A>G​(p.Lys62Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLRAD3 NM_174902.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38585618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAD3	NM_174902.4	c.184A>G	p.Lys62Glu	missense_variant	Exon 2 of 6	ENST00000315571.6	NP_777562.1
LDLRAD3	NM_001304263.2	c.47-45413A>G		intron_variant	Intron 1 of 4		NP_001291192.1
LDLRAD3	NM_001304264.2	c.-286-45413A>G		intron_variant	Intron 1 of 5		NP_001291193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLRAD3	ENST00000315571.6	c.184A>G	p.Lys62Glu	missense_variant	Exon 2 of 6	1	NM_174902.4	ENSP00000318607.5
LDLRAD3	ENST00000528989.5	c.47-45413A>G		intron_variant	Intron 1 of 4	1		ENSP00000433954.1
LDLRAD3	ENST00000524419.5	c.47-45413A>G		intron_variant	Intron 1 of 5	5		ENSP00000434313.1
LDLRAD3	ENST00000532490.1	n.147+35054A>G		intron_variant	Intron 2 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251144 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135736

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461758 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184A>G (p.K62E) alteration is located in exon 2 (coding exon 2) of the LDLRAD3 gene. This alteration results from a A to G substitution at nucleotide position 184, causing the lysine (K) at amino acid position 62 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.027
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	-0.12	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.52
Sift	Benign	0.26	T
Sift4G	Benign	0.35	T
Polyphen		0.79	P
Vest4		0.54
MutPred		0.39		Loss of ubiquitination at K62 (P = 0.0224);
MVP		0.75
MPC		0.38
ClinPred		0.41	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.52

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

Other links and lift over

dbSNP: rs765495963; hg19: chr11-36057790;