chr7-104329211-G-A

Position:

• chr7-104329211-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LHFPL3 NM_199000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
LHFPL3	NM_199000.3	c.432G>A	p.Met144Ile	missense_variant	1/3	ENST00000424859.7	NP_945351.1
LHFPL3	NM_001386065.1	c.432G>A	p.Met144Ile	missense_variant	1/4		NP_001372994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHFPL3	ENST00000424859.7	c.432G>A	p.Met144Ile	missense_variant	1/3	1	NM_199000.3	ENSP00000393128.2
LHFPL3	ENST00000401970.3	c.432G>A	p.Met144Ile	missense_variant	1/4	1		ENSP00000385374.3
LHFPL3	ENST00000683240.1	n.349G>A		non_coding_transcript_exon_variant	1/4			ENSP00000508253.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455336 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 722690

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

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	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.19	T
PrimateAI	Pathogenic	0.80	T
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	D
GERP RS		5.2
gMVP		0.87

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: rs368994276; hg19: chr7-103969659;