rs80356569

Variant names:

• chr2-26477505-G-A
• rs80356569
• NM_194248.3:c.2317C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26477505-G-A
• chr2-26477505-G-T

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.2317C>T​(p.Arg773Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,602,582 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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 (30 hom., cov: 32)
  • Exomes 𝑓: 0.014 (227 hom.)
• Consequence: OTOF NM_194248.3 missense, splice_region
• Scores: Splicing: ADA: 0.8316
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 7.79
• Publications: 10 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=0.0074848533).
• BP6: Variant 2-26477505-G-A is Benign according to our data. Variant chr2-26477505-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0501 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.2317C>T	p.Arg773Cys	missense splice_region	Exon 20 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.76C>T	p.Arg26Cys	missense splice_region	Exon 3 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2317C>T	p.Arg773Cys	missense splice_region	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.2317C>T	p.Arg773Cys	missense splice_region	Exon 20 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.76C>T	p.Arg26Cys	missense splice_region	Exon 3 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.76C>T	p.Arg26Cys	missense splice_region	Exon 2 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2377 AN: 152128 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0154 AC: 3504 AN: 227648 AF XY: 0.0158

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0139 AC: 20232 AN: 1450336 Hom.: 227 Cov.: 33 AF XY: 0.0144 AC XY: 10352 AN XY: 720362

African (AFR) AF: 0.0216 AC: 719 AN: 33364

American (AMR) AF: 0.0150 AC: 650 AN: 43212

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 1401 AN: 25876

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39340

South Asian (SAS) AF: 0.0230 AC: 1945 AN: 84456

European-Finnish (FIN) AF: 0.000782 AC: 40 AN: 51130

Middle Eastern (MID) AF: 0.0551 AC: 316 AN: 5740

European-Non Finnish (NFE) AF: 0.0127 AC: 14064 AN: 1107290

Other (OTH) AF: 0.0183 AC: 1095 AN: 59928

GnomAD4 genome AF: 0.0156 AC: 2377 AN: 152246 Hom.: 30 Cov.: 32 AF XY: 0.0153 AC XY: 1140 AN XY: 74452

African (AFR) AF: 0.0217 AC: 901 AN: 41552

American (AMR) AF: 0.0167 AC: 255 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4820

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 875 AN: 68010

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

Alfa AF: 0.0153 Hom.: 78

Bravo AF: 0.0174

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.0210 AC: 91

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.0145 AC: 1746

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.031	D
Polyphen		0.17	B
Vest4		0.73
MPC		0.49
ClinPred		0.029	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.45
Mutation Taster		=54/46	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.0		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: rs80356569; hg19: chr2-26700373; COSMIC: COSV55507243; COSMIC: COSV55507243;