OTOF p.Arg1641Leu

Variant names:

• chr2-26464907-C-A
• rs200283244
• NM_194248.3:c.4922G>T
• OTOF p.Arg1641Leu

Your query was ambiguous. Multiple possible variants found:

• chr2-26464907-C-A
• chr2-26464906-GC-AA
• chr2-26464906-GC-CA
• chr2-26464906-GC-TA
• chr2-26464906-GCG-CAA
• chr2-26464906-GCG-TAA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_194248.3(OTOF):c.4922G>T (p.Arg1641Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000376 (AC=6) in the gnomAD database across 1,597,354 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000193. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1641H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 48244); 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.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000193 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

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>T p.Arg1641Leu	missense	Exon 39 of 47	Prot: NP_919224.1 UniProt:
	OTOF NM_194323.3	MANE Plus Clinical	c.2621G>T p.Arg874Leu	missense	Exon 22 of 29	Prot: NP_919304.1 UniProt:
	OTOF NM_001287489.2		c.4922G>T p.Arg1641Leu	missense	Exon 39 of 46	Prot: NP_001274418.1 UniProt:

OTOF NM_194248.3

MANE Select

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

Exon rankExon 39 of 47

missense

Prot: NP_919224.1UniProt: Q9HC10-1

OTOF NM_194323.3

MANE Plus Clinical

HGVSc / HGVSpc.2621G>Tp.Arg874Leu

Exon rankExon 22 of 29

missense

Prot: NP_919304.1UniProt: Q9HC10-2

OTOF NM_001287489.2

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

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>T p.Arg1641Leu	missense	Exon 39 of 47	Prot: ENSP00000272371.2 UniProt:
	OTOF ENST00000339598.8	TSL:1MANE Plus Clinical	c.2621G>T p.Arg874Leu	missense	Exon 22 of 29	Prot: ENSP00000344521.3 UniProt:
	OTOF ENST00000402415.8	TSL:1	c.2681G>T p.Arg894Leu	missense	Exon 21 of 29	Prot: ENSP00000383906.4 UniProt:

OTOF ENST00000272371.7

TSL:1MANE Select

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

Exon rankExon 39 of 47

missense

Prot: ENSP00000272371.2UniProt: Q9HC10-1

OTOF ENST00000339598.8

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.2621G>Tp.Arg874Leu

Exon rankExon 22 of 29

missense

Prot: ENSP00000344521.3UniProt: Q9HC10-2

OTOF ENST00000402415.8

TSL:1

HGVSc / HGVSpc.2681G>Tp.Arg894Leu

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152140	Cov:33
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:240798	Cov:
GnomAD4 exome	AF: 0.00000277	AC:4	Hom:0	AN:1445214	Cov:31
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152140	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:174650	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.65
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.58	T
Mutation Taster	N/A	25/75	disease causing
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	4.1
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Varity_R	N/A	0.36
VESM-3B	Benign	-9.2

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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar