NM_194248.3:c.3076A>T

Variant names:

• chr2-26475409-T-A
• rs145239283
• NM_194248.3:c.3076A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.3076A>T​(p.Arg1026Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,156 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79
• Publications: 1 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=0.008550972).
• BP6: Variant 2-26475409-T-A is Benign according to our data. Variant chr2-26475409-T-A is described in ClinVar as Benign. ClinVar VariationId is 48213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00409 (622/152246) while in subpopulation AFR AF = 0.013 (539/41534). AF 95% confidence interval is 0.0121. There are 6 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Unknown 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.3076A>T	p.Arg1026Trp	missense	Exon 25 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.835A>T	p.Arg279Trp	missense	Exon 8 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3076A>T	p.Arg1026Trp	missense	Exon 25 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.3076A>T	p.Arg1026Trp	missense	Exon 25 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.835A>T	p.Arg279Trp	missense	Exon 8 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.835A>T	p.Arg279Trp	missense	Exon 7 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152128 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00100 AC: 252 AN: 250748 AF XY: 0.000773

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000342 AC: 499 AN: 1460910 Hom.: 4 Cov.: 32 AF XY: 0.000292 AC XY: 212 AN XY: 726768

African (AFR) AF: 0.0107 AC: 358 AN: 33478

American (AMR) AF: 0.00157 AC: 70 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52522

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111952

Other (OTH) AF: 0.000894 AC: 54 AN: 60380

GnomAD4 genome AF: 0.00409 AC: 622 AN: 152246 Hom.: 6 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74438

African (AFR) AF: 0.0130 AC: 539 AN: 41534

American (AMR) AF: 0.00477 AC: 73 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.00463

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.079
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.93
MPC		0.67
ClinPred		0.036	T
GERP RS		2.8
Varity_R		0.45
gMVP		0.64
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs145239283; hg19: chr2-26698277;