chr18-46477048-T-G

Position:

• chr18-46477048-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000300591.11(LOXHD1):​c.*135A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 657,744 control chromosomes in the GnomAD database, including 1,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (263 hom., cov: 33)
  • Exomes 𝑓: 0.058 (990 hom.)
• Consequence: LOXHD1 ENST00000300591.11 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.225

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 18-46477048-T-G is Benign according to our data. Variant chr18-46477048-T-G is described in ClinVar as [Benign]. Clinvar id is 1257132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOXHD1	NM_001145472.3	c.*135A>C		3_prime_UTR_variant	24/24		NP_001138944.1
LOXHD1	NM_001173129.2	c.*170A>C		3_prime_UTR_variant	10/10		NP_001166600.1
LOXHD1	NM_001308013.2	c.*170A>C		3_prime_UTR_variant	22/22		NP_001294942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000300591.11	c.*135A>C		3_prime_UTR_variant	24/24	1		ENSP00000300591
LOXHD1	ENST00000579038.6	c.*170A>C		3_prime_UTR_variant	22/22	1		ENSP00000463285
LOXHD1	ENST00000398705.7	c.*170A>C		3_prime_UTR_variant	10/10	2		ENSP00000381692

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7382 AN: 152192 Hom.: 263 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0367

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0665

GnomAD4 exome AF: 0.0577 AC: 29177 AN: 505434 Hom.: 990 Cov.: 0 AF XY: 0.0576 AC XY: 15579 AN XY: 270274

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.0481

Gnomad4 ASJ exome AF: 0.0675

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.0433

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0717

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.0485 AC: 7385 AN: 152310 Hom.: 263 Cov.: 33 AF XY: 0.0463 AC XY: 3446 AN XY: 74480

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0617

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.0373

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0712

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0553 Hom.: 42

Bravo AF: 0.0494

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74421427; hg19: chr18-44057011;