rs876657494

Variant names:

• chr18-46557413-T-C
• rs876657494
• NM_001384474.1:c.3293A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-46557413-T-C
• chr18-46557413-T-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6_Moderate

The NM_001384474.1(LOXHD1):​c.3293A>G​(p.Asn1098Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,400,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: LOXHD1 NM_001384474.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.125
• 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 -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001384474.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.05868596).
• BP6: Variant 18-46557413-T-C is Benign according to our data. Variant chr18-46557413-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 227517.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3293A>G	p.Asn1098Ser	missense	Exon 21 of 41	NP_001371403.1	A0A2R8Y7K4
	LOXHD1	NM_144612.7		c.3293A>G	p.Asn1098Ser	missense	Exon 21 of 40	NP_653213.6
	LOXHD1	NM_001145472.3		c.-41A>G		5_prime_UTR	Exon 3 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.3293A>G	p.Asn1098Ser	missense	Exon 21 of 41	ENSP00000496347.1	A0A2R8Y7K4
	LOXHD1	ENST00000300591.11	TSL:1	c.-41A>G		5_prime_UTR	Exon 3 of 24	ENSP00000300591.6	Q8IVV2-3
	LOXHD1	ENST00000536736.5	TSL:5	c.3293A>G	p.Asn1098Ser	missense	Exon 21 of 40	ENSP00000444586.1	F5GZB4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000311 AC: 5 AN: 160642 AF XY: 0.0000357

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1400034 Hom.: 0 Cov.: 33 AF XY: 0.00000579 AC XY: 4 AN XY: 690488

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.000140 AC: 5 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079114

Other (OTH) AF: 0.00 AC: 0 AN: 58184

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.9
DANN	Benign	0.89
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.13
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.022
Sift	Benign	0.95	T
Sift4G	Benign	0.84	T
Polyphen		0.18	B
Vest4		0.10
MutPred		0.35		Gain of glycosylation at N1098 (P = 0.0277)
MVP		0.072
ClinPred		0.040	T
GERP RS		1.5
Varity_R		0.034
gMVP		0.20
Mutation Taster		=91/9	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: rs876657494; hg19: chr18-44137376;