8-104490738-C-A

Variant names:

• chr8-104490738-C-A
• rs150116835
• NM_013437.5:c.2515G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013437.5(LRP12):​c.2515G>T​(p.Asp839Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D839N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LRP12 NM_013437.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32
• Publications: 8 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

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.2515G>T	p.Asp839Tyr	missense	Exon 7 of 7	NP_038465.1	Q9Y561-1
	LRP12	NM_001135703.3		c.2458G>T	p.Asp820Tyr	missense	Exon 6 of 6	NP_001129175.1	Q9Y561-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP12	ENST00000276654.10	TSL:1 MANE Select	c.2515G>T	p.Asp839Tyr	missense	Exon 7 of 7	ENSP00000276654.5	Q9Y561-1
	LRP12	ENST00000424843.6	TSL:2	c.2458G>T	p.Asp820Tyr	missense	Exon 6 of 6	ENSP00000399148.2	Q9Y561-2
	LRP12	ENST00000518375.1	TSL:2	n.1868G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250816 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.90	L
PhyloP100		7.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.094	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.44		Loss of disorder (P = 0.0587)
MVP		0.56
MPC		0.84
ClinPred		0.66	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.67
Mutation Taster		=35/65	disease causing

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: rs150116835; hg19: chr8-105502966;