11-46871557-T-C

Variant names:

• chr11-46871557-T-C
• rs2306029
• NM_002334.4:c.4660A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002334.4(LRP4):​c.4660A>G​(p.Ser1554Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,610,966 control chromosomes in the GnomAD database, including 218,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1554N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (15960 hom., cov: 31)
  • Exomes 𝑓: 0.52 (202719 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.42
• Publications: 64 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-AS1 (HGNC:44128): (LRP4 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026289523).
• BP6: Variant 11-46871557-T-C is Benign according to our data. Variant chr11-46871557-T-C is described in ClinVar as Benign. ClinVar VariationId is 304855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.4660A>G	p.Ser1554Gly	missense	Exon 31 of 38	NP_002325.2
	LRP4-AS1	NR_038909.1		n.198-1517T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.4660A>G	p.Ser1554Gly	missense	Exon 31 of 38	ENSP00000367888.1
	LRP4	ENST00000527656.1	TSL:2	n.592A>G		non_coding_transcript_exon	Exon 3 of 3
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-1517T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64975 AN: 151950 Hom.: 15955 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.481 AC: 118848 AN: 247302 AF XY: 0.492

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.521 AC: 760306 AN: 1458896 Hom.: 202719 Cov.: 43 AF XY: 0.523 AC XY: 379363 AN XY: 725626

African (AFR) AF: 0.167 AC: 5603 AN: 33456

American (AMR) AF: 0.420 AC: 18686 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14096 AN: 26082

East Asian (EAS) AF: 0.255 AC: 10090 AN: 39622

South Asian (SAS) AF: 0.517 AC: 44382 AN: 85820

European-Finnish (FIN) AF: 0.589 AC: 31390 AN: 53286

Middle Eastern (MID) AF: 0.471 AC: 2713 AN: 5764

European-Non Finnish (NFE) AF: 0.543 AC: 602851 AN: 1110134

Other (OTH) AF: 0.506 AC: 30495 AN: 60250

GnomAD4 genome AF: 0.427 AC: 64974 AN: 152070 Hom.: 15960 Cov.: 31 AF XY: 0.429 AC XY: 31918 AN XY: 74334

African (AFR) AF: 0.182 AC: 7554 AN: 41504

American (AMR) AF: 0.462 AC: 7049 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1885 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5170

South Asian (SAS) AF: 0.528 AC: 2542 AN: 4812

European-Finnish (FIN) AF: 0.578 AC: 6102 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36855 AN: 67962

Other (OTH) AF: 0.468 AC: 988 AN: 2112

Alfa AF: 0.502 Hom.: 48042

Bravo AF: 0.405

TwinsUK AF: 0.553 AC: 2052

ALSPAC AF: 0.535 AC: 2063

ESP6500AA AF: 0.195 AC: 858

ESP6500EA AF: 0.543 AC: 4671

ExAC AF: 0.477 AC: 57937

Asia WGS AF: 0.425 AC: 1481 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cenani-Lenz syndactyly syndrome Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23321396, 21121903)

Congenital myasthenic syndrome 17 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sclerosteosis 2 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.62
Sift	Benign	0.032	D
Sift4G	Benign	0.10	T
Polyphen		0.23	B
Vest4		0.24
MPC		0.57
ClinPred		0.043	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.48
Mutation Taster		=80/20	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: rs2306029; hg19: chr11-46893108; COSMIC: COSV66137634;