rs111033329

Variant names:

• chr2-26461006-C-T
• rs111033329
• NM_194248.3:c.5558G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.5558G>A​(p.Arg1853Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,383,832 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1853R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0097 (60 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.99
• Publications: 8 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_194248.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010482699).
• BP6: Variant 2-26461006-C-T is Benign according to our data. Variant chr2-26461006-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48262.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00669 (946/141400) while in subpopulation NFE AF = 0.0101 (658/65122). AF 95% confidence interval is 0.00946. There are 4 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR 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.5558G>A	p.Arg1853Gln	missense	Exon 44 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.3257G>A	p.Arg1086Gln	missense	Exon 27 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.5558G>A	p.Arg1853Gln	missense	Exon 44 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.5558G>A	p.Arg1853Gln	missense	Exon 44 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.3257G>A	p.Arg1086Gln	missense	Exon 27 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.3317G>A	p.Arg1106Gln	missense	Exon 26 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 946 AN: 141304 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0148

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00349

GnomAD2 exomes AF: 0.00720 AC: 1805 AN: 250616 AF XY: 0.00717

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00971 AC: 12062 AN: 1242432 Hom.: 60 Cov.: 36 AF XY: 0.00945 AC XY: 5820 AN XY: 616088

African (AFR) AF: 0.00174 AC: 47 AN: 26952

American (AMR) AF: 0.00205 AC: 78 AN: 38004

Ashkenazi Jewish (ASJ) AF: 0.000566 AC: 10 AN: 17680

East Asian (EAS) AF: 0.0000526 AC: 1 AN: 19014

South Asian (SAS) AF: 0.0000712 AC: 6 AN: 84234

European-Finnish (FIN) AF: 0.0280 AC: 988 AN: 35282

Middle Eastern (MID) AF: 0.00196 AC: 9 AN: 4592

European-Non Finnish (NFE) AF: 0.0108 AC: 10518 AN: 971058

Other (OTH) AF: 0.00888 AC: 405 AN: 45616

GnomAD4 genome AF: 0.00669 AC: 946 AN: 141400 Hom.: 4 Cov.: 31 AF XY: 0.00674 AC XY: 461 AN XY: 68376

African (AFR) AF: 0.00146 AC: 57 AN: 38940

American (AMR) AF: 0.00186 AC: 26 AN: 13984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3344

East Asian (EAS) AF: 0.00 AC: 0 AN: 4152

South Asian (SAS) AF: 0.00 AC: 0 AN: 3984

European-Finnish (FIN) AF: 0.0213 AC: 185 AN: 8690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0101 AC: 658 AN: 65122

Other (OTH) AF: 0.00345 AC: 7 AN: 2030

Alfa AF: 0.00849 Hom.: 21

Bravo AF: 0.00496

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00852 AC: 1035

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00747

EpiControl AF: 0.00723

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.52
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.96	P
Vest4		0.76
MVP		0.89
MPC		0.33
ClinPred		0.041	T
GERP RS		3.9
Varity_R		0.36
gMVP		0.61
Mutation Taster		=91/9	polymorphism

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: rs111033329; hg19: chr2-26683874; COSMIC: COSV55507669; COSMIC: COSV55507669;