rs7645635

Positions:

• chr3-188609767-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000617246.5(LPP):​c.1036T>C​(p.Tyr346His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,912 control chromosomes in the GnomAD database, including 14,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (7521 hom., cov: 32)
  • Exomes 𝑓: 0.019 (6777 hom.)
• Consequence: LPP ENST00000617246.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5052405E-5).
• BP6: Variant 3-188609767-T-C is Benign according to our data. Variant chr3-188609767-T-C is described in ClinVar as [Benign]. Clinvar id is 1256811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPP	NM_001375462.1	c.1036T>C	p.Tyr346His	missense_variant	7/12	ENST00000617246.5	NP_001362391.1
LOC124906316	XR_007096213.1	n.496-1997A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPP	ENST00000617246.5	c.1036T>C	p.Tyr346His	missense_variant	7/12	1	NM_001375462.1	ENSP00000478901	P1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26387 AN: 151982 Hom.: 7500 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.0469 AC: 11685 AN: 249002 Hom.: 3069 AF XY: 0.0351 AC XY: 4736 AN XY: 134970

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00350

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0193 AC: 28261 AN: 1461812 Hom.: 6777 Cov.: 34 AF XY: 0.0169 AC XY: 12301 AN XY: 727202

Gnomad4 AFR exome AF: 0.616

Gnomad4 AMR exome AF: 0.0377

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00399

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.0416

GnomAD4 genome AF: 0.174 AC: 26449 AN: 152100 Hom.: 7521 Cov.: 32 AF XY: 0.166 AC XY: 12384 AN XY: 74388

Gnomad4 AFR AF: 0.597

Gnomad4 AMR AF: 0.0748

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0396 Hom.: 2513

Bravo AF: 0.199

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.586 AC: 2581

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.0568 AC: 6900

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00528

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T;T;.;T;T
MetaRNN	Benign	0.000075	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	.;.;M;M;.
MutationTaster	Benign	0.00061	P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;.;.;.;N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;.;.;.;D
Sift4G	Benign	0.41	T;T;.;T;T
Polyphen		1.0	D;.;D;D;.
Vest4		0.85
ClinPred		0.038	T
GERP RS		6.2
Varity_R		0.081
gMVP		0.55

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: rs7645635; hg19: chr3-188327555; COSMIC: COSV57109841; COSMIC: COSV57109841;