11-46868056-C-T

Position:

• chr11-46868056-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002334.4(LRP4):​c.5010G>A​(p.Val1670=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,108 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: LRP4 NM_002334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.250

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 11-46868056-C-T is Benign according to our data. Variant chr11-46868056-C-T is described in ClinVar as [Benign]. Clinvar id is 467791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46868056-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00929 (1415/152234) while in subpopulation NFE AF= 0.014 (955/68018). AF 95% confidence interval is 0.0133. There are 13 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.5010G>A	p.Val1670=	synonymous_variant	34/38	ENST00000378623.6
LRP4-AS1	NR_038909.1	n.198-5018C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.5010G>A	p.Val1670=	synonymous_variant	34/38	1	NM_002334.4	P1
LRP4-AS1	ENST00000502049.3	n.193-5018C>T		intron_variant, non_coding_transcript_variant		2
LRP4-AS1	ENST00000531719.5	n.292-5018C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1414 AN: 152116 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0112 AC: 2828 AN: 251486 Hom.: 21 AF XY: 0.0118 AC XY: 1605 AN XY: 135920

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0143

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0125 AC: 18267 AN: 1461874 Hom.: 152 Cov.: 32 AF XY: 0.0127 AC XY: 9263 AN XY: 727238

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.00749

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00929 AC: 1415 AN: 152234 Hom.: 13 Cov.: 32 AF XY: 0.00907 AC XY: 675 AN XY: 74444

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0104 Hom.: 8

Bravo AF: 0.00861

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0156

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LRP4: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	- -

Cenani-Lenz syndactyly syndrome Benign:1

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.1
DANN	Benign	0.60

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: rs111426027; hg19: chr11-46889607;