rs199747378

Variant names:

• chr11-46869126-T-A
• rs199747378
• NM_002334.4:c.4699A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_002334.4(LRP4):​c.4699A>T​(p.Arg1567Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000337 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1567R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.01
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000401 (61/152204) while in subpopulation AMR AF = 0.0019 (29/15280). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 32 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.4699A>T	p.Arg1567Trp	missense	Exon 32 of 38	NP_002325.2	O75096
	LRP4-AS1	NR_038909.1		n.198-3948T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.4699A>T	p.Arg1567Trp	missense	Exon 32 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.4150A>T	p.Arg1384Trp	missense	Exon 29 of 35	ENSP00000528317.1
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-3948T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 251012 AF XY: 0.000280

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000330 AC: 483 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 727206

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000828 AC: 37 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000378 AC: 420 AN: 1111968

Other (OTH) AF: 0.000397 AC: 24 AN: 60392

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00190 AC: 29 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

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

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.87
MVP		0.86
MPC		1.4
ClinPred		0.17	T
GERP RS		4.9
Varity_R		0.24
gMVP		0.77
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs199747378; hg19: chr11-46890677;