11-46895950-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002334.4(LRP4):​c.1117C>G​(p.Arg373Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP4	NM_002334.4	c.1117C>G	p.Arg373Gly	missense_variant	Exon 10 of 38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.1117C>G	p.Arg373Gly	missense_variant	Exon 10 of 39		XP_016873223.1
LRP4	XM_011520103.3	c.313C>G	p.Arg105Gly	missense_variant	Exon 4 of 32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.1117C>G	p.Arg373Gly	missense_variant	Exon 10 of 38	1	NM_002334.4	ENSP00000367888.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.17	N
PhyloP100		3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.40
Sift	Benign	0.47	T
Sift4G	Benign	0.39	T
Polyphen		0.012	B
Vest4		0.62
MutPred		0.61		Loss of MoRF binding (P = 0.0334);
MVP		0.66
MPC		0.72
ClinPred		0.82	D
GERP RS		4.9
Varity_R		0.40
gMVP		0.61
Mutation Taster		=59/41	polymorphism

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;