11-36036159-T-G

Position:

• chr11-36036159-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_174902.4(LDLRAD3):​c.103T>G​(p.Phe35Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLRAD3 NM_174902.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAD3	NM_174902.4	c.103T>G	p.Phe35Val	missense_variant	2/6	ENST00000315571.6	NP_777562.1
LDLRAD3	NM_001304263.2	c.47-45494T>G		intron_variant			NP_001291192.1
LDLRAD3	NM_001304264.2	c.-286-45494T>G		intron_variant			NP_001291193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLRAD3	ENST00000315571.6	c.103T>G	p.Phe35Val	missense_variant	2/6	1	NM_174902.4	ENSP00000318607	P1
LDLRAD3	ENST00000528989.5	c.47-45494T>G		intron_variant		1		ENSP00000433954
LDLRAD3	ENST00000524419.5	c.47-45494T>G		intron_variant		5		ENSP00000434313
LDLRAD3	ENST00000532490.1	n.147+34973T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.103T>G (p.F35V) alteration is located in exon 2 (coding exon 2) of the LDLRAD3 gene. This alteration results from a T to G substitution at nucleotide position 103, causing the phenylalanine (F) at amino acid position 35 to be replaced by a valine (V). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.83		Loss of catalytic residue at F35 (P = 0.1002);
MVP		0.90
MPC		0.86
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.80

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: rs1852301628; hg19: chr11-36057709;