chr3-188609188-C-A

Position:

• chr3-188609188-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001375462.1(LPP):​c.457C>A​(p.Pro153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,460,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: LPP NM_001375462.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.940

Genes affected

LPP (HGNC:6679): (LIM domain containing preferred translocation partner in lipoma) This gene encodes a member of a subfamily of LIM domain proteins that are characterized by an N-terminal proline-rich region and three C-terminal LIM domains. The encoded protein localizes to the cell periphery in focal adhesions and may be involved in cell-cell adhesion and cell motility. This protein also shuttles through the nucleus and may function as a transcriptional co-activator. This gene is located at the junction of certain disease-related chromosomal translocations, which result in the expression of chimeric proteins that may promote tumor growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

LOC124906316 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1468989).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPP	NM_001375462.1	c.457C>A	p.Pro153Thr	missense_variant	7/12	ENST00000617246.5
LOC124906316	XR_007096213.1	n.496-1418G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPP	ENST00000617246.5	c.457C>A	p.Pro153Thr	missense_variant	7/12	1	NM_001375462.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000178 AC: 26 AN: 1460918 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726686

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The LPP p.Pro153Thr variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs780877086) and in control databases in 3 of 250148 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 1 of 9994 chromosomes (freq: 0.0001) and European (non-Finnish) in 2 of 112796 chromosomes (freq: 0.000018); it was not observed in the African, Latino, East Asian, European (Finnish), Other, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. The p.Pro153 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T;T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.93	.;.;L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D;.;.;.
REVEL	Benign	0.077
Sift	Uncertain	0.013	D;.;.;.
Sift4G	Uncertain	0.0080	D;D;.;D
Polyphen		0.82	P;.;D;D
Vest4		0.28
MutPred		0.19		Loss of catalytic residue at P152 (P = 0.0185);.;Loss of catalytic residue at P152 (P = 0.0185);Loss of catalytic residue at P152 (P = 0.0185);
MVP		0.24
ClinPred		0.56	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.39

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: rs780877086; hg19: chr3-188326976;