Genetic Variant NM_013437.5:c.1720G>C (chr8-104491533-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013437.5(LRP12):c.1720G>C(p.Val574Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V574I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRP12
NM_013437.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.35

Publications

0 publications found

Variant links:

Genes affected

LRP12 (HGNC:31708): (LDL receptor related protein 12) This gene encodes a member of the low-density lipoprotein receptor related protein family. The product of this gene is a transmembrane protein that is differentially expressed in many cancer cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

LRP12 Gene-Disease associations (from GenCC):

oculopharyngodistal myopathy 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen

LRP12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013437.5. 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
	LRP12	NM_013437.5	MANE Select	c.1720G>C	p.Val574Leu	missense	Exon 7 of 7	NP_038465.1	Q9Y561-1
	LRP12	NM_001135703.3		c.1663G>C	p.Val555Leu	missense	Exon 6 of 6	NP_001129175.1	Q9Y561-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP12	ENST00000276654.10	TSL:1 MANE Select	c.1720G>C	p.Val574Leu	missense	Exon 7 of 7	ENSP00000276654.5	Q9Y561-1
LRP12	ENST00000424843.6	TSL:2	c.1663G>C	p.Val555Leu	missense	Exon 6 of 6	ENSP00000399148.2	Q9Y561-2
LRP12	ENST00000523007.1	TSL:2	c.487G>C	p.Val163Leu	missense	Exon 3 of 3	ENSP00000429305.1	E5RIW8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443810

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32232

American (AMR)

AF:

0.00

AC:

AN:

40916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25062

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.00

AC:

AN:

83280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106044

Other (OTH)

AF:

0.00

AC:

AN:

59560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.71

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

2.0

PhyloP100

7.3

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.92

REVEL

Uncertain

0.64

Sift

Uncertain

0.0090

Sift4G

Benign

0.078

Polyphen

0.99

Vest4

0.71

MutPred

0.41

Loss of catalytic residue at V574 (P = 0.0541)

MVP

0.83

MPC

0.71

ClinPred

0.79

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.70

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over