NM_194248.3:c.5098G>C

Variant names:

• chr2-26463969-C-G
• rs199766465
• NM_194248.3:c.5098G>C

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PP4 PM3 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.5098G>C (p.Glu1700Gln) variant in OTOF is a missense variant predicted to cause a substitution of glutamic acid by glutamine at amino acid 1700. The filtering allele frequency (the lower threshold of the 95% CI of 152/44874) of the c.5098G>C (p.Glu1700Gln) is 0.2948% for East Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency the East Asian population, given it is reported as a founder mutation in the Taiwanese population (PMID:20224275). Therefore, the BS1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.85 which is above the threshold of ≥ 0.7 (PP3). This variant has been detected in at least 18 individuals with autosomal recessive nonsyndromic hearing loss. Eight individuals were homozygous for the variant (PMIDs: 20224275, 35106950). Six individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Glu841Lys, c.4961-1G>A, p.Arg1344*, p.Arg500*; PMID:28766844). Four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and confirmed in trans by parental testing (p.Pro1628Thr; PMID:34692690) (PM3_VeryStrong). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; PMID:28766844). The variant has been reported to segregate with hearing loss in multiple affected family members from two families (PP1_Strong; PMIDs: 20224275, 34692690). In summary, this variant meets the criteria to be classified as pathogenic for nonsyndromic genetic hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM3_VeryStrong, PP4, PP1_Strong; Version 2; 5/15/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345132/MONDO:0019497/023

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (1 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:3 O:1
• Conservation: PhyloP100: 7.87
• Publications: 34 publications found

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 8 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. 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
	OTOF	NM_194248.3	MANE Select	c.5098G>C	p.Glu1700Gln	missense	Exon 40 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2797G>C	p.Glu933Gln	missense	Exon 23 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.5098G>C	p.Glu1700Gln	missense	Exon 40 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5098G>C	p.Glu1700Gln	missense	Exon 40 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2797G>C	p.Glu933Gln	missense	Exon 23 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2857G>C	p.Glu953Gln	missense	Exon 22 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000512 AC: 128 AN: 249992 AF XY: 0.000421

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00691

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461470 Hom.: 1 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727024

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00302 AC: 120 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000635 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Autosomal recessive nonsyndromic hearing loss 9 (5)
1	1	-	not provided (2)
1	-	-	Auditory neuropathy spectrum disorder (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
-	1	-	not specified (1)
-	1	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.85
Sift	Benign	0.11	T
Sift4G	Benign	0.064	T
Polyphen		0.92	P
Vest4		0.84
MVP		0.95
MPC		0.51
ClinPred		0.21	T
GERP RS		4.4
Varity_R		0.44
gMVP		0.83
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs199766465; hg19: chr2-26686837;