rs2306033

chr11-46875895-G-A

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.3608C>T(p.Ala1203Val) variant causes a missense change. The variant allele was found at a frequency of 0.155 in 1,613,704 control chromosomes in the GnomAD database, including 27,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1203T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2454 hom., cov: 31)
  • Exomes 𝑓: 0.16 (25225 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.72

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=3.744471E-5).
• BP6: Variant 11-46875895-G-A is Benign according to our data. Variant chr11-46875895-G-A is described in ClinVar as [Benign]. Clinvar id is 304869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.3608C>T	p.Ala1203Val	missense_variant	26/38	ENST00000378623.6
LRP4	XM_017017734.2	c.3608C>T	p.Ala1203Val	missense_variant	26/39
LRP4	XM_011520103.3	c.2804C>T	p.Ala935Val	missense_variant	20/32
LRP4	XM_011520104.3	c.1373C>T	p.Ala458Val	missense_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.3608C>T	p.Ala1203Val	missense_variant	26/38	1	NM_002334.4	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21059 AN: 151922 Hom.: 2443 Cov.: 31

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.209 AC: 52497 AN: 251278 Hom.: 8800 AF XY: 0.200 AC XY: 27189 AN XY: 135822

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.195

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.157 AC: 229334 AN: 1461664 Hom.: 25225 Cov.: 36 AF XY: 0.157 AC XY: 113960 AN XY: 727168

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.0586

Gnomad4 EAS exome AF: 0.618

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.139 AC: 21072 AN: 152040 Hom.: 2454 Cov.: 31 AF XY: 0.149 AC XY: 11068 AN XY: 74306

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.119

Alfa AF: 0.133 Hom.: 4890

Bravo AF: 0.137

TwinsUK AF: 0.127 AC: 470

ALSPAC AF: 0.136 AC: 525

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.122 AC: 1051

ExAC AF: 0.194 AC: 23606

Asia WGS AF: 0.313 AC: 1085 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Benign	0.66
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.000037	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.23
Sift	Benign	0.91	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.54
ClinPred		0.011	T
GERP RS		5.7
Varity_R		0.027
gMVP		0.26

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: rs2306033; hg19: chr11-46897446; COSMIC: COSV66135213; COSMIC: COSV66135213;