3-188609182-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001375462.1(LPP):c.451T>C(p.Ser151Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,611,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: LPP NM_001375462.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.281

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007114589).
• BP6: Variant 3-188609182-T-C is Benign according to our data. Variant chr3-188609182-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 998374.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 254 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPP	NM_001375462.1	c.451T>C	p.Ser151Pro	missense_variant	7/12	ENST00000617246.5
LOC124906316	XR_007096213.1	n.496-1412A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPP	ENST00000617246.5	c.451T>C	p.Ser151Pro	missense_variant	7/12	1	NM_001375462.1	P1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000393 AC: 98 AN: 249548 Hom.: 0 AF XY: 0.000282 AC XY: 38 AN XY: 134788

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.000116

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: 0.000165 AC: 241 AN: 1459344 Hom.: 1 Cov.: 31 AF XY: 0.000134 AC XY: 97 AN XY: 725608

Gnomad4 AFR exome AF: 0.00629

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74370

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000273 Hom.: 0

Bravo AF: 0.00183

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acute myeloid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 13, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

LPP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.91
DEOGEN2	Benign	0.0064	T;.;T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.54	T;T;T;.;T
MetaRNN	Benign	0.0054	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N;N;.;.;.
REVEL	Benign	0.079
Sift	Benign	0.24	T;D;.;.;.
Sift4G	Benign	0.46	T;D;T;.;T
Polyphen		0.0030	B;.;.;D;D
Vest4		0.27
MVP		0.27
ClinPred		0.031	T
GERP RS		4.5
Varity_R		0.072
gMVP		0.24

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: rs35746269; hg19: chr3-188326970;