rs144350829

chr11-46859181-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_002334.4(LRP4):c.5520T>C(p.His1840=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,614,120 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: LRP4 NM_002334.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.10

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 11-46859181-A-G is Benign according to our data. Variant chr11-46859181-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304846.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152232) while in subpopulation NFE AF= 0.00129 (88/68004). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.5520T>C	p.His1840=	synonymous_variant	38/38	ENST00000378623.6
LRP4-AS1	NR_038909.1	n.197+12464A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.5520T>C	p.His1840=	synonymous_variant	38/38	1	NM_002334.4	P1
LRP4-AS1	ENST00000502049.3	n.192+12464A>G		intron_variant, non_coding_transcript_variant		2
LRP4	ENST00000529604.1	n.463T>C		non_coding_transcript_exon_variant	2/2	2
LRP4-AS1	ENST00000531719.5	n.291+6235A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00115 AC: 290 AN: 251354 Hom.: 0 AF XY: 0.00132 AC XY: 179 AN XY: 135860

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00109 AC: 1595 AN: 1461888 Hom.: 2 Cov.: 31 AF XY: 0.00107 AC XY: 775 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152232 Hom.: 0 Cov.: 31 AF XY: 0.000819 AC XY: 61 AN XY: 74440

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000646

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cenani-Lenz syndactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

LRP4-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.20
Dann	Benign	0.43

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

Other links and lift over

dbSNP: rs144350829; hg19: chr11-46880732;