rs117936904

Positions:

chr11-46864526-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_002334.4(LRP4):c.5165T>A(p.Leu1722His) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,611,148 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 50 hom., cov: 32)

Exomes 𝑓: 0.021 ( 388 hom. )

Consequence

LRP4
NM_002334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.74

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=0.007769525).

BP6

Variant 11-46864526-A-T is Benign according to our data. Variant chr11-46864526-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 304849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46864526-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0178 (2711/152350) while in subpopulation NFE AF= 0.0228 (1552/68036). AF 95% confidence interval is 0.0219. There are 50 homozygotes in gnomad4. There are 1366 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4 linkuse as main transcript	c.5165T>A	p.Leu1722His	missense_variant	36/38	ENST00000378623.6
LRP4-AS1	NR_038909.1 linkuse as main transcript	n.198-8548A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LRP4	ENST00000378623.6 linkuse as main transcript	c.5165T>A	p.Leu1722His	missense_variant	36/38	1	NM_002334.4	P1
LRP4-AS1	ENST00000502049.3 linkuse as main transcript	n.193-8548A>T		intron_variant, non_coding_transcript_variant		2
LRP4-AS1	ENST00000531719.5 linkuse as main transcript	n.292-8548A>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2713

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0619

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0194

AC:

4875

AN:

250854

Hom.:

AF XY:

0.0196

AC XY:

2656

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00568

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0209

AC:

30531

AN:

1458798

Hom.:

388

Cov.:

AF XY:

0.0204

AC XY:

14826

AN XY:

726026

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.0163

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00505

Gnomad4 FIN exome

AF:

0.0590

Gnomad4 NFE exome

AF:

0.0221

Gnomad4 OTH exome

AF:

0.0198

GnomAD4 genome

AF:

0.0178

AC:

2711

AN:

152350

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1366

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00365

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0619

Gnomad4 NFE

AF:

0.0228

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0209

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0186

AC:

2257

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0247

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0078

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.69

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

Sift4G

Benign

0.074

Polyphen

0.99

Vest4

0.35

MPC

0.26

ClinPred

0.022

GERP RS

6.0

Varity_R

0.33

gMVP

0.84

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