rs765240067

Variant names:

• chr11-46874885-G-A
• rs765240067
• NM_002334.4:c.4144C>T
• LRP4 p.Pro1382Ser

Your query was ambiguous. Multiple possible variants found:

• chr11-46874885-G-A
• chr11-46874885-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_002334.4(LRP4):​c.4144C>T​(p.Pro1382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1382A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.40
• Publications: 3 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20092916).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000028 (41/1461874) while in subpopulation SAS AF = 0.000406 (35/86258). AF 95% confidence interval is 0.0003. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 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.4144C>T	p.Pro1382Ser	missense	Exon 28 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.4144C>T	p.Pro1382Ser	missense	Exon 28 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.3595C>T	p.Pro1199Ser	missense	Exon 25 of 35	ENSP00000528317.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251330 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.35
Sift	Benign	0.67	T
Sift4G	Benign	0.67	T
Varity_R		0.11
gMVP		0.46
Mutation Taster		=67/33	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

dbSNP: rs765240067;

hg19: chr11-46896436;

COSMIC: COSV66137009;

COSMIC: COSV66137009;