Genetic Variant LHFPL3:p.Met144Ile (chr7-104329211-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_199000.3(LHFPL3):c.432G>A(p.Met144Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LHFPL3
NM_199000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.66

Publications

0 publications found

Variant links:

Genes affected

LHFPL3 (HGNC:6589): (LHFPL tetraspan subfamily member 3) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in one LHFP-like gene result in deafness in humans and mice, and a second LHFP-like gene is fused to a high-mobility group gene in a translocation-associated lipoma. A partial gene fragment named LHFPL4 corresponds to a portion of the first exon of this gene. [provided by RefSeq, Jul 2008]

LHFPL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHFPL3	NM_199000.3 link	c.432G>A	p.Met144Ile	missense_variant	Exon 1 of 3	ENST00000424859.7	NP_945351.1	Q86UP9
LHFPL3	NM_001386065.1 link	c.432G>A	p.Met144Ile	missense_variant	Exon 1 of 4		NP_001372994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LHFPL3	ENST00000424859.7 link	c.432G>A	p.Met144Ile	missense_variant	Exon 1 of 3	1	NM_199000.3	ENSP00000393128.2	Q86UP9
LHFPL3	ENST00000401970.3 link	c.432G>A	p.Met144Ile	missense_variant	Exon 1 of 4	1		ENSP00000385374.3	A1L384
LHFPL3	ENST00000683240.1 link	n.349G>A		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000508253.1	A0A804HL93

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

245032

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.87e-7

AC:

AN:

1455336

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722690

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33306

American (AMR)

AF:

0.00

AC:

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

85910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107174

Other (OTH)

AF:

0.00

AC:

AN:

59982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.432G>A (p.M144I) alteration is located in exon 1 (coding exon 1) of the LHFPL3 gene. This alteration results from a G to A substitution at nucleotide position 432, causing the methionine (M) at amino acid position 144 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

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.19

PhyloP100

9.7

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.052

T;D

Vest4

0.83

MutPred

0.68

Loss of catalytic residue at M130 (P = 0.0601);Loss of catalytic residue at M130 (P = 0.0601);

MVP

0.83

ClinPred

0.98

GERP RS

5.2

gMVP

0.87

Mutation Taster

=38/62

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over