rs373924055

Variant names:

• chr18-46518215-G-A
• rs373924055
• NM_001384474.1:c.5313C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-46518215-G-A
• chr18-46518215-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001384474.1(LOXHD1):​c.5313C>T​(p.Gly1771Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,551,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1771G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: LOXHD1 NM_001384474.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -2.62
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 77

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-46518215-G-A is Benign according to our data. Variant chr18-46518215-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47943.
• BP7: Synonymous conserved (PhyloP=-2.62 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384474.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	NM_001384474.1	MANE Select	c.5313C>T	p.Gly1771Gly	synonymous	Exon 34 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.5127C>T	p.Gly1709Gly	synonymous	Exon 33 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.1980C>T	p.Gly660Gly	synonymous	Exon 16 of 24	NP_001138944.1	Q8IVV2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXHD1	ENST00000642948.1	MANE Select	c.5313C>T	p.Gly1771Gly	synonymous	Exon 34 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.1980C>T	p.Gly660Gly	synonymous	Exon 16 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000579038.6	TSL:1	c.1692C>T	p.Gly564Gly	synonymous	Exon 14 of 22	ENSP00000463285.1	J3QKX9

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00152 AC: 240 AN: 158388 AF XY: 0.00161

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.0000884

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00195 AC: 2731 AN: 1399382 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 1321 AN XY: 690190

African (AFR) AF: 0.000285 AC: 9 AN: 31598

American (AMR) AF: 0.00129 AC: 46 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 85 AN: 25182

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79236

European-Finnish (FIN) AF: 0.00173 AC: 85 AN: 49272

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00223 AC: 2405 AN: 1078954

Other (OTH) AF: 0.00164 AC: 95 AN: 58002

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74410

African (AFR) AF: 0.000458 AC: 19 AN: 41510

American (AMR) AF: 0.00111 AC: 17 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.00138

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	2	Autosomal recessive nonsyndromic hearing loss 77 (3)
-	-	1	LOXHD1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.1
DANN	Benign	0.53
PhyloP100		-2.6
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs373924055; hg19: chr18-44098178; COSMIC: COSV56060844;