rs148865136

Positions:

• chr11-46864509-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BS1_Supporting

The NM_002334.4(LRP4):​c.5182A>G​(p.Ile1728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.40

Genes affected

LRP4 (HGNC:6696): (LDL receptor related protein 4) This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]

LRP4-AS1 (HGNC:44128): (LRP4 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRP4
• BP4: Computational evidence support a benign effect (MetaRNN=0.050016463).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000447 (68/152268) while in subpopulation AMR AF= 0.00131 (20/15296). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.5182A>G	p.Ile1728Val	missense_variant	36/38	ENST00000378623.6
LRP4-AS1	NR_038909.1	n.198-8565T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.5182A>G	p.Ile1728Val	missense_variant	36/38	1	NM_002334.4	P1
LRP4-AS1	ENST00000502049.3	n.193-8565T>C		intron_variant, non_coding_transcript_variant		2
LRP4-AS1	ENST00000531719.5	n.292-8565T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000371 AC: 93 AN: 250946 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135608

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000436 AC: 637 AN: 1461242 Hom.: 0 Cov.: 30 AF XY: 0.000446 AC XY: 324 AN XY: 727014

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000464

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74454

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000527 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.5182A>G (p.I1728V) alteration is located in exon 36 (coding exon 36) of the LRP4 gene. This alteration results from a A to G substitution at nucleotide position 5182, causing the isoleucine (I) at amino acid position 1728 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cenani-Lenz syndactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1728 of the LRP4 protein (p.Ile1728Val). This variant is present in population databases (rs148865136, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 288220). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRP4 protein function. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.6
DANN	Benign	0.82
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.25
Sift	Benign	0.46	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.35
MVP		0.42
MPC		0.060
ClinPred		0.0099	T
GERP RS		3.6
Varity_R		0.026
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148865136; hg19: chr11-46886060;