chr18-46477048-T-G

Variant names:

• chr18-46477048-T-G
• rs74421427
• ENST00000300591:c.*135A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145472.3(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 NM_001145472.3 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LOXHD1	NM_001384474.1	c.*424A>C		downstream_gene_variant		ENST00000642948.1	NP_001371403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOXHD1	ENST00000642948.1	c.*424A>C		downstream_gene_variant			NM_001384474.1	ENSP00000496347.1

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 AC: 189 AN: 13734

Gnomad4 AMR exome AF: 0.0481 AC: 1279 AN: 26598

Gnomad4 ASJ exome AF: 0.0675 AC: 1130 AN: 16740

Gnomad4 EAS exome AF: 0.0154 AC: 487 AN: 31622

Gnomad4 SAS exome AF: 0.0433 AC: 2237 AN: 51604

Gnomad4 FIN exome AF: 0.0236 AC: 962 AN: 40784

Gnomad4 NFE exome AF: 0.0717 AC: 21021 AN: 293146

Gnomad4 Remaining exome AF: 0.0603 AC: 1703 AN: 28224

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 AC: 0.0137767 AN: 0.0137767

Gnomad4 AMR AF: 0.0617 AC: 0.0617236 AN: 0.0617236

Gnomad4 ASJ AF: 0.0602 AC: 0.0601959 AN: 0.0601959

Gnomad4 EAS AF: 0.0155 AC: 0.015456 AN: 0.015456

Gnomad4 SAS AF: 0.0373 AC: 0.0373134 AN: 0.0373134

Gnomad4 FIN AF: 0.0226 AC: 0.0226159 AN: 0.0226159

Gnomad4 NFE AF: 0.0712 AC: 0.0711535 AN: 0.0711535

Gnomad4 OTH AF: 0.0658 AC: 0.0658144 AN: 0.0658144

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.84
Mutation Taster		=100/0	polymorphism (auto)

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;