rs765240067

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

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 (★★).

• 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:2
• Conservation: PhyloP100: 6.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.20092916).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4	c.4144C>T	p.Pro1382Ser	missense_variant	28/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.4144C>T	p.Pro1382Ser	missense_variant	28/39		XP_016873223.1
LRP4	XM_011520103.3	c.3340C>T	p.Pro1114Ser	missense_variant	22/32		XP_011518405.1
LRP4	XM_011520104.3	c.1909C>T	p.Pro637Ser	missense_variant	13/23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.4144C>T	p.Pro1382Ser	missense_variant	28/38	1	NM_002334.4	ENSP00000367888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251330 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135832

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 SAS exome AF: 0.000425

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 573237). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. This variant is present in population databases (rs765240067, gnomAD 0.04%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1382 of the LRP4 protein (p.Pro1382Ser). -

Computational scores

Source: dbNSFP v4.3

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
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.35
Sift	Benign	0.67	T
Sift4G	Benign	0.67	T
Polyphen		0.0080	B
Vest4		0.49
MVP		0.70
MPC		0.57
ClinPred		0.34	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.46

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: rs765240067; hg19: chr11-46896436; COSMIC: COSV66137009; COSMIC: COSV66137009;