LRP4 p.Gly333Arg

Variant names:

• chr11-46896261-C-G
• NM_002334.4:c.997G>C
• LRP4 p.Gly333Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-46896261-C-G
• chr11-46896261-C-T
• chr11-46896259-CCC-ACG
• chr11-46896259-CCC-GCG
• chr11-46896259-CCC-TCG
• chr11-46896259-CCC-TCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002334.4(LRP4):​c.997G>C​(p.Gly333Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 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, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 17

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen, 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

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.997G>C	p.Gly333Arg	missense	Exon 9 of 38	NP_002325.2	O75096

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.997G>C	p.Gly333Arg	missense	Exon 9 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.997G>C	p.Gly333Arg	missense	Exon 9 of 35	ENSP00000528317.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.060	T
Varity_R		0.54
gMVP		0.65
Mutation Taster		=83/17	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-46917812;