rs149082597

Positions:

• chr11-46859041-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_002334.4(LRP4):​c.5660C>G​(p.Ser1887Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 5.34

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 -6 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=0.016842842).
• BP6: Variant 11-46859041-G-C is Benign according to our data. Variant chr11-46859041-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282957.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00114 (173/152304) while in subpopulation AMR AF= 0.00203 (31/15298). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.5660C>G	p.Ser1887Cys	missense_variant	38/38	ENST00000378623.6
LRP4-AS1	NR_038909.1	n.197+12324G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.5660C>G	p.Ser1887Cys	missense_variant	38/38	1	NM_002334.4	P1
LRP4-AS1	ENST00000502049.3	n.192+12324G>C		intron_variant, non_coding_transcript_variant		2
LRP4	ENST00000529604.1	n.603C>G		non_coding_transcript_exon_variant	2/2	2
LRP4-AS1	ENST00000531719.5	n.291+6095G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152186 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251234 Hom.: 1 AF XY: 0.00107 AC XY: 145 AN XY: 135778

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00144 AC: 2108 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00140 AC XY: 1017 AN XY: 727236

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152304 Hom.: 1 Cov.: 31 AF XY: 0.000832 AC XY: 62 AN XY: 74476

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Meniere disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center for Computational Biology & Bioinformatics, University of California, San Diego

Jun 03, 2024

- -

Cenani-Lenz syndactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

LRP4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.34
MVP		0.88
MPC		0.16
ClinPred		0.052	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.32

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: rs149082597; hg19: chr11-46880592;