7-104736851-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_199000.3(LHFPL3):c.622T>C(p.Phe208Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHFPL3 NM_199000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHFPL3	NM_199000.3	c.622T>C	p.Phe208Leu	missense_variant	2/3	ENST00000424859.7
LHFPL3	NM_001386065.1	c.622T>C	p.Phe208Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHFPL3	ENST00000424859.7	c.622T>C	p.Phe208Leu	missense_variant	2/3	1	NM_199000.3	P1
LHFPL3	ENST00000401970.3	c.622T>C	p.Phe208Leu	missense_variant	2/4	1
LHFPL3	ENST00000684090.1	n.200T>C		non_coding_transcript_exon_variant	2/3
LHFPL3	ENST00000683240.1	c.*229T>C		3_prime_UTR_variant, NMD_transcript_variant	3/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 11, 2022

The c.622T>C (p.F208L) alteration is located in exon 2 (coding exon 2) of the LHFPL3 gene. This alteration results from a T to C substitution at nucleotide position 622, causing the phenylalanine (F) at amino acid position 208 to be replaced by a leucine (L). 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	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.084	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.82
MutPred		0.76		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.39
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-104377298;