18-46560273-C-T

Position:

chr18-46560273-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001384474.1(LOXHD1):c.2871G>A(p.Ser957Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,548,014 control chromosomes in the GnomAD database, including 9 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 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

LOXHD1
NM_001384474.1 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.356

Variant links:

Genes affected

LOXHD1 (HGNC:26521): (lipoxygenase homology PLAT domains 1) This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

LOXHD1 links:

LOXHD1 (HGNC:):

LOXHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 18-46560273-C-T is Benign according to our data. Variant chr18-46560273-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226715.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr18-46560273-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.356 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00449 (683/152068) while in subpopulation AFR AF= 0.0154 (642/41568). AF 95% confidence interval is 0.0145. There are 6 homozygotes in gnomad4. There are 303 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	Protein	UniProt
LOXHD1	NM_001384474.1 linkuse as main transcript	c.2871G>A	p.Ser957Ser	synonymous_variant	19/41	ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LOXHD1	ENST00000642948.1 linkuse as main transcript	c.2871G>A	p.Ser957Ser	synonymous_variant	19/41		NM_001384474.1	ENSP00000496347.1	A0A2R8Y7K4
LOXHD1	ENST00000536736.5 linkuse as main transcript	c.2871G>A	p.Ser957Ser	synonymous_variant	19/40	5		ENSP00000444586.1	F5GZB4
LOXHD1	ENST00000441551.6 linkuse as main transcript	c.2599-2784G>A		intron_variant		5		ENSP00000387621.2	Q8IVV2-1
LOXHD1	ENST00000335730.6 linkuse as main transcript	n.2184G>A		non_coding_transcript_exon_variant	12/27	2

Frequencies

GnomAD3 genomes

AF:

0.00448

AC:

681

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00109

AC:

172

AN:

157990

Hom.:

AF XY:

0.000649

AC XY:

AN XY:

83180

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.000526

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000492

Gnomad OTH exome

AF:

0.000668

GnomAD4 exome

AF:

0.000484

AC:

675

AN:

1395946

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

286

AN XY:

688652

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.000101

Gnomad4 NFE exome

AF:

0.0000474

Gnomad4 OTH exome

AF:

0.000672

GnomAD4 genome

AF:

0.00449

AC:

683

AN:

152068

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.00184

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.00518

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 77

Uncertain:1Benign: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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 15, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

p.Ser957Ser in exon 19 of LOXHD1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1.53% (43/2804) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; rs181591912). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over