6-35805539-A-G

Position:

• chr6-35805539-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182548.4(LHFPL5):​c.-132A>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 0.00585 in 846,592 control chromosomes in the GnomAD database, including 28 homozygotes. 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 0.0052 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (22 hom.)
• Consequence: LHFPL5 NM_182548.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.04

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-35805539-A-G is Benign according to our data. Variant chr6-35805539-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356483.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00519 (789/152074) while in subpopulation NFE AF= 0.0087 (591/67958). AF 95% confidence interval is 0.00812. There are 6 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHFPL5	NM_182548.4	c.-132A>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.-132A>G		5_prime_UTR_variant	1/4	1	NM_182548.4	P1
LHFPL5	ENST00000651132.1	c.-132A>G		splice_region_variant, 5_prime_UTR_variant	4/7			P1
LHFPL5	ENST00000651676.1	c.-132A>G		5_prime_UTR_variant	1/4			P1
LHFPL5	ENST00000651994.1	c.-132A>G		5_prime_UTR_variant, NMD_transcript_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 151956 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00576

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00599 AC: 4163 AN: 694518 Hom.: 22 Cov.: 9 AF XY: 0.00574 AC XY: 2094 AN XY: 364698

Gnomad4 AFR exome AF: 0.000968

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00767

Gnomad4 NFE exome AF: 0.00751

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.00519 AC: 789 AN: 152074 Hom.: 6 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74330

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00367

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00576

Gnomad4 NFE AF: 0.00870

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00757 Hom.: 3

Bravo AF: 0.00490

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.0
DANN	Benign	0.81

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: rs143126474; hg19: chr6-35773316;