6-35805671-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_182548.4(LHFPL5):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LHFPL5 NM_182548.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.15

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-35805671-A-G is Pathogenic according to our data. Variant chr6-35805671-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402282.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-35805671-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHFPL5	NM_182548.4	c.1A>G	p.Met1?	start_lost	1/4	ENST00000360215.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHFPL5	ENST00000360215.3	c.1A>G	p.Met1?	start_lost	1/4	1	NM_182548.4	P1
LHFPL5	ENST00000651132.1	c.1A>G	p.Met1?	start_lost	4/7			P1
LHFPL5	ENST00000651676.1	c.1A>G	p.Met1?	start_lost	1/4			P1
LHFPL5	ENST00000651994.1	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 67 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	LHFPL5 c.1A>G, p.M1V alters the first codon of LHFPL5, leading to loss of the translation start. The entire N-terminal cytoplasmic domain of the protein lises between codon 1 and the next Met at codon 28. The variant is homozygous in 5 Palestinian children with pre-lingual severe to profound hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.077	B;B
Vest4		0.97
MutPred		1.0		Loss of catalytic residue at M1 (P = 0.0395);Loss of catalytic residue at M1 (P = 0.0395);
MVP		0.75
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.86

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: rs1060499810; hg19: chr6-35773448;