8-104491533-C-T

Variant names:

• chr8-104491533-C-T
• rs769678128
• NM_013437.5:c.1720G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_013437.5(LRP12):​c.1720G>A​(p.Val574Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,443,810 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: 0.0000076 (0 hom.)
• Consequence: LRP12 NM_013437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4046406).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP12	NM_013437.5	c.1720G>A	p.Val574Ile	missense_variant	Exon 7 of 7	ENST00000276654.10	NP_038465.1
LRP12	NM_001135703.3	c.1663G>A	p.Val555Ile	missense_variant	Exon 6 of 6		NP_001129175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP12	ENST00000276654.10	c.1720G>A	p.Val574Ile	missense_variant	Exon 7 of 7	1	NM_013437.5	ENSP00000276654.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000299 AC: 7 AN: 233754 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1443810 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 717952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1720G>A (p.V574I) alteration is located in exon 7 (coding exon 7) of the LRP12 gene. This alteration results from a G to A substitution at nucleotide position 1720, causing the valine (V) at amino acid position 574 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0072	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.38	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D;D;D
Sift4G	Benign	0.093	T;T;.
Polyphen		0.99	D;D;.
Vest4		0.50
MutPred		0.35		.;Loss of catalytic residue at V574 (P = 0.0215);.;
MVP		0.65
MPC		0.68
ClinPred		0.48	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.53

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: rs769678128; hg19: chr8-105503761;