rs118009068

Variant names:

• chr11-46895950-G-A
• rs118009068
• NM_002334.4:c.1117C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-46895950-G-A
• chr11-46895950-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000378623.6(LRP4):​c.1117C>T​(p.Arg373Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,888 control chromosomes in the GnomAD database, including 427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (24 hom., cov: 33)
  • Exomes 𝑓: 0.022 (403 hom.)
• Consequence: LRP4 ENST00000378623.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.41
• Publications: 13 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 Gene-Disease associations (from GenCC):

• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• congenital myasthenic syndrome 17

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis 2

  Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011091918).
• BP6: Variant 11-46895950-G-A is Benign according to our data. Variant chr11-46895950-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304890.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 = 0.0171 (2598/152290) while in subpopulation NFE AF = 0.026 (1766/68024). AF 95% confidence interval is 0.025. There are 24 homozygotes in GnomAd4. There are 1236 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378623.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.1117C>T	p.Arg373Trp	missense	Exon 10 of 38	NP_002325.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.1117C>T	p.Arg373Trp	missense	Exon 10 of 38	ENSP00000367888.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2603 AN: 152172 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0183 AC: 4599 AN: 251196 AF XY: 0.0194

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0219 AC: 31976 AN: 1461598 Hom.: 403 Cov.: 33 AF XY: 0.0219 AC XY: 15920 AN XY: 727114

African (AFR) AF: 0.00385 AC: 129 AN: 33480

American (AMR) AF: 0.0118 AC: 529 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 702 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0176 AC: 1518 AN: 86258

European-Finnish (FIN) AF: 0.0139 AC: 741 AN: 53188

Middle Eastern (MID) AF: 0.0251 AC: 145 AN: 5768

European-Non Finnish (NFE) AF: 0.0243 AC: 26999 AN: 1111958

Other (OTH) AF: 0.0201 AC: 1211 AN: 60386

GnomAD4 genome AF: 0.0171 AC: 2598 AN: 152290 Hom.: 24 Cov.: 33 AF XY: 0.0166 AC XY: 1236 AN XY: 74456

African (AFR) AF: 0.00524 AC: 218 AN: 41566

American (AMR) AF: 0.0164 AC: 251 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4830

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0260 AC: 1766 AN: 68024

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0224 Hom.: 143

Bravo AF: 0.0162

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.00591 AC: 26

ESP6500EA AF: 0.0273 AC: 235

ExAC AF: 0.0187 AC: 2275

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0268

EpiControl AF: 0.0268

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	0.31	N
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.63
Sift	Benign	0.050	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.31
MPC		1.5
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.56
Mutation Taster		=74/26	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: rs118009068; hg19: chr11-46917501; COSMIC: COSV66135898; COSMIC: COSV66135898;