rs117936904

Variant names:

• chr11-46864526-A-T
• rs117936904
• NM_002334.4:c.5165T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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:7
• Conservation: PhyloP100: 6.74
• Publications: 12 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 -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 304849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR,SD gene

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.5165T>A	p.Leu1722His	missense	Exon 36 of 38	NP_002325.2	O75096
	LRP4-AS1	NR_038909.1		n.198-8548A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.5165T>A	p.Leu1722His	missense	Exon 36 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.4616T>A	p.Leu1539His	missense	Exon 33 of 35	ENSP00000528317.1
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-8548A>T		intron	N/A

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

GnomAD2 exomes AF: 0.0194 AC: 4875 AN: 250854 AF XY: 0.0196

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 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

African (AFR) AF: 0.00311 AC: 104 AN: 33430

American (AMR) AF: 0.0139 AC: 621 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 426 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39670

South Asian (SAS) AF: 0.00505 AC: 435 AN: 86206

European-Finnish (FIN) AF: 0.0590 AC: 3143 AN: 53314

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5758

European-Non Finnish (NFE) AF: 0.0221 AC: 24501 AN: 1109300

Other (OTH) AF: 0.0198 AC: 1196 AN: 60280

GnomAD4 genome AF: 0.0178 AC: 2711 AN: 152350 Hom.: 50 Cov.: 32 AF XY: 0.0183 AC XY: 1366 AN XY: 74492

African (AFR) AF: 0.00365 AC: 152 AN: 41588

American (AMR) AF: 0.0148 AC: 227 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.0619 AC: 657 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1552 AN: 68036

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cenani-Lenz syndactyly syndrome (1)
-	-	1	Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.7
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
Mutation Taster		=54/46	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117936904; hg19: chr11-46886077;