NM_194248.3:c.4767C>T

Variant names:

• chr2-26465704-G-A
• rs80356578
• NM_194248.3:c.4767C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.4767C>T​(p.Arg1589Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,250 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (95 hom., cov: 33)
  • Exomes 𝑓: 0.011 (569 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -2.18
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-26465704-G-A is Benign according to our data. Variant chr2-26465704-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 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.4767C>T	p.Arg1589Arg	synonymous	Exon 38 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2466C>T	p.Arg822Arg	synonymous	Exon 21 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4767C>T	p.Arg1589Arg	synonymous	Exon 38 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.4767C>T	p.Arg1589Arg	synonymous	Exon 38 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2466C>T	p.Arg822Arg	synonymous	Exon 21 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2526C>T	p.Arg842Arg	synonymous	Exon 20 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2377 AN: 152250 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0301 AC: 7569 AN: 251462 AF XY: 0.0250

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0402

Gnomad FIN exome AF: 0.0872

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0107 AC: 15583 AN: 1461882 Hom.: 569 Cov.: 32 AF XY: 0.00986 AC XY: 7172 AN XY: 727246

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.108 AC: 4836 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26136

East Asian (EAS) AF: 0.0319 AC: 1267 AN: 39700

South Asian (SAS) AF: 0.00341 AC: 294 AN: 86258

European-Finnish (FIN) AF: 0.0829 AC: 4427 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00354 AC: 3941 AN: 1112006

Other (OTH) AF: 0.0114 AC: 686 AN: 60396

GnomAD4 genome AF: 0.0156 AC: 2379 AN: 152368 Hom.: 95 Cov.: 33 AF XY: 0.0194 AC XY: 1445 AN XY: 74506

African (AFR) AF: 0.00322 AC: 134 AN: 41594

American (AMR) AF: 0.0427 AC: 653 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.0424 AC: 220 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4832

European-Finnish (FIN) AF: 0.0901 AC: 956 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00539 AC: 367 AN: 68042

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00674 Hom.: 9

Bravo AF: 0.0142

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.011
DANN	Benign	0.75
PhyloP100		-2.2
Mutation Taster		=92/8	polymorphism (auto)

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: rs80356578; hg19: chr2-26688572; COSMIC: COSV55514045;