rs2306033

Variant names:

• chr11-46875895-G-A
• rs2306033
• NM_002334.4:c.3608C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002334.4(LRP4):​c.3608C>T​(p.Ala1203Val) variant causes a missense change. The variant allele was found at a frequency of 0.155 in 1,613,704 control chromosomes in the GnomAD database, including 27,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1203E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2454 hom., cov: 31)
  • Exomes 𝑓: 0.16 (25225 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.72
• Publications: 46 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• congenital myasthenic syndrome 17

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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=3.744471E-5).
• BP6: Variant 11-46875895-G-A is Benign according to our data. Variant chr11-46875895-G-A is described in ClinVar as Benign. ClinVar VariationId is 304869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

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.3608C>T	p.Ala1203Val	missense	Exon 26 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.3608C>T	p.Ala1203Val	missense	Exon 26 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.3059C>T	p.Ala1020Val	missense	Exon 23 of 35	ENSP00000528317.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21059 AN: 151922 Hom.: 2443 Cov.: 31

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.209 AC: 52497 AN: 251278 AF XY: 0.200

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.157 AC: 229334 AN: 1461664 Hom.: 25225 Cov.: 36 AF XY: 0.157 AC XY: 113960 AN XY: 727168

African (AFR) AF: 0.0219 AC: 733 AN: 33476

American (AMR) AF: 0.377 AC: 16851 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0586 AC: 1532 AN: 26134

East Asian (EAS) AF: 0.618 AC: 24531 AN: 39700

South Asian (SAS) AF: 0.201 AC: 17339 AN: 86246

European-Finnish (FIN) AF: 0.230 AC: 12267 AN: 53410

Middle Eastern (MID) AF: 0.106 AC: 614 AN: 5768

European-Non Finnish (NFE) AF: 0.132 AC: 146443 AN: 1111834

Other (OTH) AF: 0.149 AC: 9024 AN: 60388

GnomAD4 genome AF: 0.139 AC: 21072 AN: 152040 Hom.: 2454 Cov.: 31 AF XY: 0.149 AC XY: 11068 AN XY: 74306

African (AFR) AF: 0.0302 AC: 1252 AN: 41514

American (AMR) AF: 0.233 AC: 3556 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3093 AN: 5124

South Asian (SAS) AF: 0.204 AC: 982 AN: 4812

European-Finnish (FIN) AF: 0.249 AC: 2636 AN: 10566

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8986 AN: 67956

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.136 Hom.: 6851

Bravo AF: 0.137

TwinsUK AF: 0.127 AC: 470

ALSPAC AF: 0.136 AC: 525

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.122 AC: 1051

ExAC AF: 0.194 AC: 23606

Asia WGS AF: 0.313 AC: 1085 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.112

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.66
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.000037	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.23
Sift	Benign	0.91	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.54
ClinPred		0.011	T
GERP RS		5.7
Varity_R		0.027
gMVP		0.26
Mutation Taster		=90/10	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: rs2306033; hg19: chr11-46897446; COSMIC: COSV66135213; COSMIC: COSV66135213;