rs118009068

Variant names:

• chr11-46895950-G-A
• rs118009068
• NM_002334.4:c.1117C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-46895950-G-A
• chr11-46895950-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002334.4(LRP4):​c.1117C>T​(p.Arg373Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,888 control chromosomes in the GnomAD database, including 427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (24 hom., cov: 33)
  • Exomes 𝑓: 0.022 (403 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.41
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• congenital myasthenic syndrome 17

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis 2

  Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011091918).
• BP6: Variant 11-46895950-G-A is Benign according to our data. Variant chr11-46895950-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 304890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2598/152290) while in subpopulation NFE AF = 0.026 (1766/68024). AF 95% confidence interval is 0.025. There are 24 homozygotes in GnomAd4. There are 1236 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4	c.1117C>T	p.Arg373Trp	missense_variant	Exon 10 of 38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.1117C>T	p.Arg373Trp	missense_variant	Exon 10 of 39		XP_016873223.1
LRP4	XM_011520103.3	c.313C>T	p.Arg105Trp	missense_variant	Exon 4 of 32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.1117C>T	p.Arg373Trp	missense_variant	Exon 10 of 38	1	NM_002334.4	ENSP00000367888.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2603 AN: 152172 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0183 AC: 4599 AN: 251196 AF XY: 0.0194

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0219 AC: 31976 AN: 1461598 Hom.: 403 Cov.: 33 AF XY: 0.0219 AC XY: 15920 AN XY: 727114

African (AFR) AF: 0.00385 AC: 129 AN: 33480

American (AMR) AF: 0.0118 AC: 529 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 702 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0176 AC: 1518 AN: 86258

European-Finnish (FIN) AF: 0.0139 AC: 741 AN: 53188

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5768

European-Non Finnish (NFE) AF: 0.0243 AC: 26999 AN: 1111958

Other (OTH) AF: 0.0201 AC: 1211 AN: 60386

GnomAD4 genome AF: 0.0171 AC: 2598 AN: 152290 Hom.: 24 Cov.: 33 AF XY: 0.0166 AC XY: 1236 AN XY: 74456

African (AFR) AF: 0.00524 AC: 218 AN: 41566

American (AMR) AF: 0.0164 AC: 251 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4830

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0260 AC: 1766 AN: 68024

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0224 Hom.: 143

Bravo AF: 0.0162

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.00591 AC: 26

ESP6500EA AF: 0.0273 AC: 235

ExAC AF: 0.0187 AC: 2275

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0268

EpiControl AF: 0.0268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 19, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30327840) -

Cenani-Lenz syndactyly syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	0.31	N
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.63
Sift	Benign	0.050	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.31
MPC		1.5
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.56
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

dbSNP: rs118009068; hg19: chr11-46917501; COSMIC: COSV66135898; COSMIC: COSV66135898;