rs72897663

Positions:

chr11-46894628-T-G

Variant summary

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

The ENST00000378623.6(LRP4):c.1501A>C(p.Asn501His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,212 control chromosomes in the GnomAD database, including 1,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N501N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1330 hom. )

Consequence

LRP4
ENST00000378623.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.67

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:

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=0.0063460767).

BP6

Variant 11-46894628-T-G is Benign according to our data. Variant chr11-46894628-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 304886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46894628-T-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRP4	NM_002334.4 linkuse as main transcript	c.1501A>C	p.Asn501His	missense_variant	12/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2 linkuse as main transcript	c.1501A>C	p.Asn501His	missense_variant	12/39		XP_016873223.1
LRP4	XM_011520103.3 linkuse as main transcript	c.697A>C	p.Asn233His	missense_variant	6/32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6 linkuse as main transcript	c.1501A>C	p.Asn501His	missense_variant	12/38	1	NM_002334.4	ENSP00000367888	P1

Frequencies

GnomAD3 genomes

AF:

0.0316

AC:

4808

AN:

152182

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00767

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0311

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.0749

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0432

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0345

AC:

8591

AN:

249058

Hom.:

186

AF XY:

0.0351

AC XY:

4724

AN XY:

134636

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0370

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.0714

Gnomad NFE exome

AF:

0.0447

Gnomad OTH exome

AF:

0.0488

GnomAD4 exome

AF:

0.0397

AC:

57935

AN:

1460912

Hom.:

1330

Cov.:

AF XY:

0.0392

AC XY:

28494

AN XY:

726676

show subpopulations

Gnomad4 AFR exome

AF:

0.00621

Gnomad4 AMR exome

AF:

0.0262

Gnomad4 ASJ exome

AF:

0.0360

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0137

Gnomad4 FIN exome

AF:

0.0752

Gnomad4 NFE exome

AF:

0.0429

Gnomad4 OTH exome

AF:

0.0384

GnomAD4 genome

AF:

0.0315

AC:

4803

AN:

152300

Hom.:

129

Cov.:

AF XY:

0.0317

AC XY:

2364

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00763

Gnomad4 AMR

AF:

0.0311

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0130

Gnomad4 FIN

AF:

0.0749

Gnomad4 NFE

AF:

0.0432

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0411

Hom.:

236

Bravo

AF:

0.0281

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0407

AC:

157

ESP6500AA

AF:

0.00818

AC:

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0334

AC:

4051

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0063

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.94

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.42

Sift

Benign

0.072

Sift4G

Benign

0.13

Polyphen

0.29

Vest4

0.23

MPC

0.84

ClinPred

0.015

GERP RS

5.7

Varity_R

0.29

gMVP

0.67

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