rs61740776

Variant names:

• chr2-26473257-T-C
• rs61740776
• NM_194248.3:c.3608A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.3608A>G​(p.Asn1203Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,348 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.016 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (51 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.49
• 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

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005012989).
• BP6: Variant 2-26473257-T-C is Benign according to our data. Variant chr2-26473257-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

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.3608A>G	p.Asn1203Ser	missense	Exon 29 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.1367A>G	p.Asn456Ser	missense	Exon 12 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3608A>G	p.Asn1203Ser	missense	Exon 29 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.3608A>G	p.Asn1203Ser	missense	Exon 29 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1367A>G	p.Asn456Ser	missense	Exon 12 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.1367A>G	p.Asn456Ser	missense	Exon 11 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2374 AN: 152042 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00391 AC: 979 AN: 250338 AF XY: 0.00293

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00156 AC: 2285 AN: 1461188 Hom.: 51 Cov.: 33 AF XY: 0.00134 AC XY: 976 AN XY: 726892

African (AFR) AF: 0.0556 AC: 1860 AN: 33478

American (AMR) AF: 0.00280 AC: 125 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111938

Other (OTH) AF: 0.00364 AC: 220 AN: 60382

GnomAD4 genome AF: 0.0156 AC: 2380 AN: 152160 Hom.: 54 Cov.: 33 AF XY: 0.0149 AC XY: 1107 AN XY: 74382

African (AFR) AF: 0.0551 AC: 2286 AN: 41504

American (AMR) AF: 0.00438 AC: 67 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67980

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00742 Hom.: 53

Bravo AF: 0.0170

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (2)
-	-	2	not specified (2)
-	-	1	Bilateral sensorineural hearing impairment (1)
-	-	1	OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.51	N
PhyloP100		3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.033	B
Vest4		0.45
MVP		0.43
MPC		0.59
ClinPred		0.035	T
GERP RS		4.9
PromoterAI		-0.049	Neutral
Varity_R		0.13
gMVP		0.52
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61740776; hg19: chr2-26696125;