chr11-46896317-A-G

Position:

• chr11-46896317-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000378623.6(LRP4):​c.941T>C​(p.Leu314Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00957 in 1,614,034 control chromosomes in the GnomAD database, including 1,280 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (676 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (604 hom.)
• Consequence: LRP4 ENST00000378623.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.79

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP4. . Gene score misZ 3.0632 (greater than the threshold 3.09). Trascript score misZ 5.2056 (greater than threshold 3.09). GenCC has associacion of gene with postsynaptic congenital myasthenic syndrome, sclerosteosis, Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016334653).
• BP6: Variant 11-46896317-A-G is Benign according to our data. Variant chr11-46896317-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 304892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46896317-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4	c.941T>C	p.Leu314Ser	missense_variant	9/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.941T>C	p.Leu314Ser	missense_variant	9/39		XP_016873223.1
LRP4	XM_011520103.3	c.137T>C	p.Leu46Ser	missense_variant	3/32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.941T>C	p.Leu314Ser	missense_variant	9/38	1	NM_002334.4	ENSP00000367888	P1

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7801 AN: 152214 Hom.: 676 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0139 AC: 3492 AN: 251174 Hom.: 296 AF XY: 0.0101 AC XY: 1367 AN XY: 135792

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00522 AC: 7623 AN: 1461702 Hom.: 604 Cov.: 33 AF XY: 0.00446 AC XY: 3246 AN XY: 727184

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0513 AC: 7818 AN: 152332 Hom.: 676 Cov.: 33 AF XY: 0.0492 AC XY: 3665 AN XY: 74482

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0340

Alfa AF: 0.00700 Hom.: 115

Bravo AF: 0.0597

ESP6500AA AF: 0.175 AC: 769

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0169 AC: 2055

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Cenani-Lenz syndactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.017	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	0.99	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.10
Sift	Benign	0.96	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.76
ClinPred		0.0097	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs7926667; hg19: chr11-46917868;