11-46871557-T-C

Position:

chr11-46871557-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.43 ( 15960 hom., cov: 31)

Exomes 𝑓: 0.52 ( 202719 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.42

Variant links:

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 links:

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

LRP4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP4. . Gene score misZ 3.0632 (greater than the threshold 3.09). Trascript score misZ 5.2056 (greater than threshold 3.09). GenCC has associacion of gene with postsynaptic congenital myasthenic syndrome, sclerosteosis, Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17.

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4 linkuse as main transcript	c.4660A>G	p.Ser1554Gly	missense_variant	31/38	ENST00000378623.6	NP_002325.2
LRP4-AS1	NR_038909.1 linkuse as main transcript	n.198-1517T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LRP4	ENST00000378623.6 linkuse as main transcript	c.4660A>G	p.Ser1554Gly	missense_variant	31/38	1	NM_002334.4	ENSP00000367888	P1
LRP4-AS1	ENST00000502049.3 linkuse as main transcript	n.193-1517T>C		intron_variant, non_coding_transcript_variant		2
LRP4	ENST00000527656.1 linkuse as main transcript	n.592A>G		non_coding_transcript_exon_variant	3/3	2
LRP4-AS1	ENST00000531719.5 linkuse as main transcript	n.292-1517T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

64975

AN:

151950

Hom.:

15955

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.481

AC:

118848

AN:

247302

Hom.:

30468

AF XY:

0.492

AC XY:

65681

AN XY:

133598

show subpopulations

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 SAS exome

AF:

0.526

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.:

AF XY:

0.523

AC XY:

379363

AN XY:

725626

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.420

Gnomad4 ASJ exome

AF:

0.540

Gnomad4 EAS exome

AF:

0.255

Gnomad4 SAS exome

AF:

0.517

Gnomad4 FIN exome

AF:

0.589

Gnomad4 NFE exome

AF:

0.543

Gnomad4 OTH exome

AF:

0.506

GnomAD4 genome

AF:

0.427

AC:

64974

AN:

152070

Hom.:

15960

Cov.:

AF XY:

0.429

AC XY:

31918

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.182

Gnomad4 AMR

AF:

0.462

Gnomad4 ASJ

AF:

0.543

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.528

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.542

Gnomad4 OTH

AF:

0.468

Alfa

AF:

0.519

Hom.:

37256

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

LINK: link

Submissions by phenotype

Cenani-Lenz syndactyly syndrome

Benign:2

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 23321396, 21121903) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myasthenic syndrome 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Sclerosteosis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.00026

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.62

Sift

Benign

0.032

Sift4G

Benign

0.10

Polyphen

0.23

Vest4

0.24

MPC

0.57

ClinPred

0.043

GERP RS

5.8

Varity_R

0.20

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over