3-185514496-T-C

Position:

chr3-185514496-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBS1_SupportingBS2_Supporting

The NM_139248.3(LIPH):c.1008A>G(p.Ile336Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,503,626 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 6 hom. )

Consequence

LIPH
NM_139248.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.25

Variant links:

Genes affected

LIPH (HGNC:18483): (lipase H) This gene encodes a membrane-bound member of the mammalian triglyceride lipase family. It catalyzes the production of 2-acyl lysophosphatidic acid (LPA), which is a lipid mediator with diverse biological properties that include platelet aggregation, smooth muscle contraction, and stimulation of cell proliferation and motility. [provided by RefSeq, Jul 2008]

LIPH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056887597).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000319 (431/1351340) while in subpopulation MID AF= 0.0218 (121/5538). AF 95% confidence interval is 0.0187. There are 6 homozygotes in gnomad4_exome. There are 239 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LIPH	NM_139248.3 linkuse as main transcript	c.1008A>G	p.Ile336Met	missense_variant	8/10	ENST00000296252.9
LIPH	XM_006713529.5 linkuse as main transcript	c.918A>G	p.Ile306Met	missense_variant	7/9
LIPH	XM_017005852.3 linkuse as main transcript	c.906A>G	p.Ile302Met	missense_variant	7/9
LIPH	XM_011512530.4 linkuse as main transcript	c.879A>G	p.Ile293Met	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LIPH	ENST00000296252.9 linkuse as main transcript	c.1008A>G	p.Ile336Met	missense_variant	8/10	1	NM_139248.3	P1
LIPH	ENST00000424591.6 linkuse as main transcript	c.906A>G	p.Ile302Met	missense_variant	7/9	1
LIPH	ENST00000435679.1 linkuse as main transcript	c.42A>G	p.Ile14Met	missense_variant	2/4	5

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000366

AC:

AN:

251368

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000319

AC:

431

AN:

1351340

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

239

AN XY:

678450

show subpopulations

Gnomad4 AFR exome

AF:

0.0000957

Gnomad4 AMR exome

AF:

0.000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000607

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000724

GnomAD4 genome

AF:

0.000236

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000489

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1008A>G (p.I336M) alteration is located in exon 8 (coding exon 8) of the LIPH gene. This alteration results from a A to G substitution at nucleotide position 1008, causing the isoleucine (I) at amino acid position 336 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 336 of the LIPH protein (p.Ile336Met). This variant is present in population databases (rs150976315, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with LIPH-related conditions. ClinVar contains an entry for this variant (Variation ID: 2037509). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LIPH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.15

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.11

B;B

Vest4

0.25

MVP

0.80

MPC

0.13

ClinPred

0.033

GERP RS

2.4

Varity_R

0.060

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over