chr6-35814627-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_182548.4(LHFPL5):​c.494C>T​(p.Thr165Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,022 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: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

LHFPL5
NM_182548.4 missense

Scores

10
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:2

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a topological_domain Extracellular (size 28) in uniprot entity LHPL5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_182548.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LHFPL5NM_182548.4 linkuse as main transcriptc.494C>T p.Thr165Met missense_variant 2/4 ENST00000360215.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LHFPL5ENST00000360215.3 linkuse as main transcriptc.494C>T p.Thr165Met missense_variant 2/41 NM_182548.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251392
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000968
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000118
AC:
173
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.000113
AC XY:
82
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.000147
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000153
Hom.:
0
Bravo
AF:
0.000102
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 67 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2006- -
Pathogenic, no assertion criteria providedclinical testingDr.Nikuei Genetic Center-- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 25, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23217710, 27260575, 31835641, 16752389) -
LHFPL5-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 07, 2023The LHFPL5 c.494C>T variant is predicted to result in the amino acid substitution p.Thr165Met. This variant was reported in the homozygous state in six individuals from a consanguineous family with nonsyndromic hearing loss (Kalay. 2006. PubMed ID: 16752389). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.31
D
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.9
D;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0050
D;.
Polyphen
1.0
D;D
Vest4
0.97
MVP
0.61
MPC
1.1
ClinPred
0.68
D
GERP RS
5.2
Varity_R
0.80

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104893976; hg19: chr6-35782404; COSMIC: COSV100798916; API