rs149941106

Positions:

• chr6-35805713-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 BP4_Strong BP6 BS1

The NM_182548.4(LHFPL5):​c.43C>T​(p.His15Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: LHFPL5 NM_182548.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.83

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 Likely_benign. Variant got -5 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=0.045241386).
• BP6: Variant 6-35805713-C-T is Benign according to our data. Variant chr6-35805713-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000906 (138/152318) while in subpopulation AMR AF= 0.00235 (36/15302). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHFPL5	NM_182548.4	c.43C>T	p.His15Tyr	missense_variant	1/4	ENST00000360215.3	NP_872354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHFPL5	ENST00000360215.3	c.43C>T	p.His15Tyr	missense_variant	1/4	1	NM_182548.4	ENSP00000353346.1
LHFPL5	ENST00000651132.1	c.43C>T	p.His15Tyr	missense_variant	4/7			ENSP00000498322.1
LHFPL5	ENST00000651676.1	c.43C>T	p.His15Tyr	missense_variant	1/4			ENSP00000498699.1
LHFPL5	ENST00000651994.1	n.43C>T		non_coding_transcript_exon_variant	1/4			ENSP00000498310.1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000676 AC: 170 AN: 251462 Hom.: 0 AF XY: 0.000743 AC XY: 101 AN XY: 135916

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000413 AC XY: 300 AN XY: 727248

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000344

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74486

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000506 Hom.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	This variant is associated with the following publications: (PMID: 29752989) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 08, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.His15Tyr vari ant in LHFPL5 has been previously reported in 4 individuals with hearing loss by our laboratory; however, none of them had a variant affecting the other copy of the gene and one of these individuals had an alternate etiology of the hearing loss. This variant has been identified in 0.2% (67/34420 and 44/24030) of Latino and African chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs149941106). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, while the clinical significance of the p.His15Tyr variant is uncertain, the frequency data in the general population suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Autosomal recessive nonsyndromic hearing loss 67 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Uncertain	0.21	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.067	T;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.98	D;D
Vest4		0.89
MVP		0.63
MPC		1.1
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.40

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: rs149941106; hg19: chr6-35773490;