rs200283244

Variant names:

• chr2-26464907-C-T
• rs200283244
• NM_194248.3:c.4922G>A
• OTOF p.Arg1641His

Your query was ambiguous. Multiple possible variants found:

• chr2-26464907-C-T
• chr2-26464907-C-A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). B3_Supporting

The NM_194248.3(OTOF):c.4922G>A (p.Arg1641His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000482 (AC=77) in the gnomAD database across 1,597,470 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000979. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1641= (synonymous): Likely_benign (ClinVar VariationId 2897397, 1 star); p.R1641= (synonymous): Likely_benign (ClinVar VariationId 4705054, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.14
• Publications: 2 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 Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

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

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTOF NM_194248.3	MANE Select	c.4922G>A p.Arg1641His	missense	Exon 39 of 47	Prot: NP_919224.1 UniProt:
	OTOF NM_194323.3	MANE Plus Clinical	c.2621G>A p.Arg874His	missense	Exon 22 of 29	Prot: NP_919304.1 UniProt:
	OTOF NM_001287489.2		c.4922G>A p.Arg1641His	missense	Exon 39 of 46	Prot: NP_001274418.1 UniProt:

OTOF NM_194248.3

MANE Select

HGVSc / HGVSpc.4922G>Ap.Arg1641His

Exon rankExon 39 of 47

missense

Prot: NP_919224.1UniProt: Q9HC10-1

OTOF NM_194323.3

MANE Plus Clinical

HGVSc / HGVSpc.2621G>Ap.Arg874His

Exon rankExon 22 of 29

missense

Prot: NP_919304.1UniProt: Q9HC10-2

OTOF NM_001287489.2

HGVSc / HGVSpc.4922G>Ap.Arg1641His

Exon rankExon 39 of 46

missense

Prot: NP_001274418.1UniProt: Q9HC10-5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTOF ENST00000272371.7	TSL:1MANE Select	c.4922G>A p.Arg1641His	missense	Exon 39 of 47	Prot: ENSP00000272371.2 UniProt:
	OTOF ENST00000339598.8	TSL:1MANE Plus Clinical	c.2621G>A p.Arg874His	missense	Exon 22 of 29	Prot: ENSP00000344521.3 UniProt:
	OTOF ENST00000402415.8	TSL:1	c.2681G>A p.Arg894His	missense	Exon 21 of 29	Prot: ENSP00000383906.4 UniProt:

OTOF ENST00000272371.7

TSL:1MANE Select

HGVSc / HGVSpc.4922G>Ap.Arg1641His

Exon rankExon 39 of 47

missense

Prot: ENSP00000272371.2UniProt: Q9HC10-1

OTOF ENST00000339598.8

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.2621G>Ap.Arg874His

Exon rankExon 22 of 29

missense

Prot: ENSP00000344521.3UniProt: Q9HC10-2

OTOF ENST00000402415.8

TSL:1

HGVSc / HGVSpc.2681G>Ap.Arg894His

Exon rankExon 21 of 29

missense

Prot: ENSP00000383906.4UniProt: A0A2U3TZT7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000592	AC:9	Hom:0	AN:152140	Cov:33
GnomAD2 exomes	AF: 0.000203	AC:49	Hom:	AN:240798	Cov:
GnomAD4 exome	AF: 0.0000477	AC:69	Hom:0	AN:1445212	Cov:31
GnomAD4 genome	AF: 0.0000525	AC:8	Hom:0	AN:152258	Cov:33
TOPMed (Bravo)	AF: 0.0000793	AC:21	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000183	AC:32	Hom:0	AN:174650	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000410	AC:5	Hom:0	AN:122276	Cov:
Turkish Variome	AF: 0.000355	AC:2	Hom:0	AN:5164	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000109	12	110342	0.0000809	15	185516

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.081
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.028
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.78	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	4.1
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.26
Sift	Benign	0.049	D
Sift4G	Uncertain	0.035	D
Varity_R	N/A	0.21
VESM-3B	Benign	-7.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200283244;

hg19: chr2-26687775;

COSMIC: COSV55516687;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar