6-35805608-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_182548.4(LHFPL5):c.-63C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,574,914 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (93 hom.)
• Consequence: LHFPL5 NM_182548.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.567

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00582 (886/152356) while in subpopulation NFE AF= 0.00663 (451/68034). AF 95% confidence interval is 0.00612. There are 9 homozygotes in gnomad4. There are 430 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHFPL5	NM_182548.4	c.-63C>G		5_prime_UTR_variant	1/4	ENST00000360215.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHFPL5	ENST00000360215.3	c.-63C>G		5_prime_UTR_variant	1/4	1	NM_182548.4	P1
LHFPL5	ENST00000651132.1	c.-63C>G		5_prime_UTR_variant	4/7			P1
LHFPL5	ENST00000651676.1	c.-63C>G		5_prime_UTR_variant	1/4			P1
LHFPL5	ENST00000651994.1	c.-63C>G		5_prime_UTR_variant, NMD_transcript_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 889 AN: 152238 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00700 AC: 9963 AN: 1422558 Hom.: 93 Cov.: 26 AF XY: 0.00710 AC XY: 5034 AN XY: 709384

Gnomad4 AFR exome AF: 0.00208

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.0596

Gnomad4 EAS exome AF: 0.000583

Gnomad4 SAS exome AF: 0.00406

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152356 Hom.: 9 Cov.: 32 AF XY: 0.00577 AC XY: 430 AN XY: 74502

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.00683 Hom.: 0

Bravo AF: 0.00646

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.8
Dann	Benign	0.74

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: rs41270084; hg19: chr6-35773385;