rs72897663

Positions:

• chr11-46894628-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002334.4(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 NM_002334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.67

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]

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=0.0063460767).
• 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	UniProt
LRP4	NM_002334.4	c.1501A>C	p.Asn501His	missense_variant	12/38	ENST00000378623.6
LRP4	XM_017017734.2	c.1501A>C	p.Asn501His	missense_variant	12/39
LRP4	XM_011520103.3	c.697A>C	p.Asn233His	missense_variant	6/32

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4808 AN: 152182 Hom.: 129 Cov.: 32

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

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.: 33 AF XY: 0.0392 AC XY: 28494 AN XY: 726676

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.: 32 AF XY: 0.0317 AC XY: 2364 AN XY: 74476

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: 36

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0334 AC: 4051

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0063	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.072	T
Sift4G	Benign	0.13	T
Polyphen		0.29	B
Vest4		0.23
MPC		0.84
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs72897663; hg19: chr11-46916179; COSMIC: COSV66139446; COSMIC: COSV66139446;