rs148865136

Variant names:

• chr11-46864509-T-C
• rs148865136
• NM_002334.4:c.5182A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_002334.4(LRP4):​c.5182A>G​(p.Ile1728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.40
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050016463).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000447 (68/152268) while in subpopulation AMR AF = 0.00131 (20/15296). AF 95% confidence interval is 0.000866. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.5182A>G	p.Ile1728Val	missense	Exon 36 of 38	NP_002325.2	O75096
	LRP4-AS1	NR_038909.1		n.198-8565T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.5182A>G	p.Ile1728Val	missense	Exon 36 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.4633A>G	p.Ile1545Val	missense	Exon 33 of 35	ENSP00000528317.1
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-8565T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000371 AC: 93 AN: 250946 AF XY: 0.000347

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000436 AC: 637 AN: 1461242 Hom.: 0 Cov.: 30 AF XY: 0.000446 AC XY: 324 AN XY: 727014

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.00110 AC: 49 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.000464 AC: 516 AN: 1111496

Other (OTH) AF: 0.000944 AC: 57 AN: 60374

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74454

African (AFR) AF: 0.000313 AC: 13 AN: 41554

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000526 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cenani-Lenz syndactyly syndrome (1)
-	1	-	Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.6
DANN	Benign	0.82
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.25
Sift	Benign	0.46	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.35
MVP		0.42
MPC		0.060
ClinPred		0.0099	T
GERP RS		3.6
Varity_R		0.026
gMVP		0.53
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148865136; hg19: chr11-46886060;