NM_194248.3:c.2381G>A

Variant names:

• chr2-26477441-C-T
• rs80356592
• NM_194248.3:c.2381G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.2381G>A​(p.Arg794His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,596,440 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5 O:1
• Conservation: PhyloP100: 5.89
• Publications: 14 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

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014693469).
• BP6: Variant 2-26477441-C-T is Benign according to our data. Variant chr2-26477441-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21835.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152174) while in subpopulation NFE AF = 0.00209 (142/67992). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,Unknown gene

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.2381G>A	p.Arg794His	missense	Exon 20 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.140G>A	p.Arg47His	missense	Exon 3 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2381G>A	p.Arg794His	missense	Exon 20 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.2381G>A	p.Arg794His	missense	Exon 20 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.140G>A	p.Arg47His	missense	Exon 3 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.140G>A	p.Arg47His	missense	Exon 2 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00109 AC: 241 AN: 220574 AF XY: 0.00115

Gnomad AFR exome AF: 0.000521

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00208 AC: 2999 AN: 1444266 Hom.: 8 Cov.: 33 AF XY: 0.00198 AC XY: 1420 AN XY: 716558

African (AFR) AF: 0.000180 AC: 6 AN: 33254

American (AMR) AF: 0.000920 AC: 39 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39060

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83216

European-Finnish (FIN) AF: 0.0000982 AC: 5 AN: 50896

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5734

European-Non Finnish (NFE) AF: 0.00257 AC: 2834 AN: 1104204

Other (OTH) AF: 0.00186 AC: 111 AN: 59742

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74390

African (AFR) AF: 0.000530 AC: 22 AN: 41526

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000922 AC: 4

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.000907 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	Autosomal recessive nonsyndromic hearing loss 9 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.019	D
Polyphen		0.94	P
Vest4		0.88
MVP		0.93
MPC		0.57
ClinPred		0.054	T
GERP RS		4.7
Varity_R		0.45
gMVP		0.63
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80356592; hg19: chr2-26700309;