6-35805743-G-T

Variant names:

• chr6-35805743-G-T
• NM_182548.4:c.73G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_182548.4(LHFPL5):​c.73G>T​(p.Val25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHFPL5 NM_182548.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

Genes affected

LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) 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 this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain LHFPL tetraspan subfamily member 5 protein (size 218) in uniprot entity LHPL5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_182548.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35681808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHFPL5	NM_182548.4	c.73G>T	p.Val25Leu	missense_variant	Exon 1 of 4	ENST00000360215.3	NP_872354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHFPL5	ENST00000360215.3	c.73G>T	p.Val25Leu	missense_variant	Exon 1 of 4	1	NM_182548.4	ENSP00000353346.1
LHFPL5	ENST00000651132.1	c.73G>T	p.Val25Leu	missense_variant	Exon 4 of 7			ENSP00000498322.1
LHFPL5	ENST00000651676.1	c.73G>T	p.Val25Leu	missense_variant	Exon 1 of 4			ENSP00000498699.1
LHFPL5	ENST00000651994.1	n.73G>T		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000498310.1

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 provided Uncertain:1

Jan 10, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val25Leu variant in LHFPL5 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.021	D;.
Polyphen		0.12	B;B
Vest4		0.30
MutPred		0.64		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.41
MPC		0.56
ClinPred		0.66	D
GERP RS		3.5
Varity_R		0.22

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: chr6-35773520;