rs2306029

Variant names:

• chr11-46871557-T-C
• rs2306029
• NM_002334.4:c.4660A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-46871557-T-C
• chr11-46871557-T-A

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.4660A>G​(p.Ser1554Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,610,966 control chromosomes in the GnomAD database, including 218,679 homozygotes. In-silico tool predicts 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. S1554N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (15960 hom., cov: 31)
  • Exomes 𝑓: 0.52 (202719 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.42
• Publications: 64 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-AS1 (HGNC:44128): (LRP4 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026289523).
• BP6: Variant 11-46871557-T-C is Benign according to our data. Variant chr11-46871557-T-C is described in ClinVar as Benign. ClinVar VariationId is 304855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 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.4660A>G	p.Ser1554Gly	missense	Exon 31 of 38	NP_002325.2	O75096
	LRP4-AS1	NR_038909.1		n.198-1517T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.4660A>G	p.Ser1554Gly	missense	Exon 31 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.4111A>G	p.Ser1371Gly	missense	Exon 28 of 35	ENSP00000528317.1
	LRP4	ENST00000527656.1	TSL:2	n.592A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64975 AN: 151950 Hom.: 15955 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.481 AC: 118848 AN: 247302 AF XY: 0.492

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.521 AC: 760306 AN: 1458896 Hom.: 202719 Cov.: 43 AF XY: 0.523 AC XY: 379363 AN XY: 725626

African (AFR) AF: 0.167 AC: 5603 AN: 33456

American (AMR) AF: 0.420 AC: 18686 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14096 AN: 26082

East Asian (EAS) AF: 0.255 AC: 10090 AN: 39622

South Asian (SAS) AF: 0.517 AC: 44382 AN: 85820

European-Finnish (FIN) AF: 0.589 AC: 31390 AN: 53286

Middle Eastern (MID) AF: 0.471 AC: 2713 AN: 5764

European-Non Finnish (NFE) AF: 0.543 AC: 602851 AN: 1110134

Other (OTH) AF: 0.506 AC: 30495 AN: 60250

GnomAD4 genome AF: 0.427 AC: 64974 AN: 152070 Hom.: 15960 Cov.: 31 AF XY: 0.429 AC XY: 31918 AN XY: 74334

African (AFR) AF: 0.182 AC: 7554 AN: 41504

American (AMR) AF: 0.462 AC: 7049 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1885 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5170

South Asian (SAS) AF: 0.528 AC: 2542 AN: 4812

European-Finnish (FIN) AF: 0.578 AC: 6102 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36855 AN: 67962

Other (OTH) AF: 0.468 AC: 988 AN: 2112

Alfa AF: 0.502 Hom.: 48042

Bravo AF: 0.405

TwinsUK AF: 0.553 AC: 2052

ALSPAC AF: 0.535 AC: 2063

ESP6500AA AF: 0.195 AC: 858

ESP6500EA AF: 0.543 AC: 4671

ExAC AF: 0.477 AC: 57937

Asia WGS AF: 0.425 AC: 1481 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.62
Sift	Benign	0.032	D
Sift4G	Benign	0.10	T
Polyphen		0.23	B
Vest4		0.24
MPC		0.57
ClinPred		0.043	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.48
Mutation Taster		=80/20	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: rs2306029; hg19: chr11-46893108; COSMIC: COSV66137634;