rs117936904

Positions:

• chr11-46864526-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.74

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP4
• 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	c.5165T>A	p.Leu1722His	missense_variant	36/38	ENST00000378623.6
LRP4-AS1	NR_038909.1	n.198-8548A>T		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2713 AN: 152232 Hom.: 50 Cov.: 32

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.: 77 AF XY: 0.0196 AC XY: 2656 AN XY: 135570

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.: 29 AF XY: 0.0204 AC XY: 14826 AN XY: 726026

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.: 50 Cov.: 32 AF XY: 0.0183 AC XY: 1366 AN XY: 74492

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.: 33

Bravo AF: 0.0141

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0186 AC: 2257

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0247

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.074	T
Polyphen		0.99	D
Vest4		0.35
MPC		0.26
ClinPred		0.022	T
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

Other links and lift over

dbSNP: rs117936904; hg19: chr11-46886077;