rs45442103

Variant names:

• chr2-26460909-G-A
• rs45442103
• NM_194248.3:c.5655C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26460909-G-A
• chr2-26460909-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.5655C>T​(p.Arg1885Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 1,614,042 control chromosomes in the GnomAD database, including 2,762 homozygotes. In-silico tool predicts 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 0.046 (202 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2560 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.0630
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-26460909-G-A is Benign according to our data. Variant chr2-26460909-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.063 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 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.5655C>T	p.Arg1885Arg	synonymous	Exon 44 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.3354C>T	p.Arg1118Arg	synonymous	Exon 27 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.5655C>T	p.Arg1885Arg	synonymous	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.5655C>T	p.Arg1885Arg	synonymous	Exon 44 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.3354C>T	p.Arg1118Arg	synonymous	Exon 27 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.3414C>T	p.Arg1138Arg	synonymous	Exon 26 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6942 AN: 152160 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0458 AC: 11508 AN: 251370 AF XY: 0.0468

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0645

Gnomad NFE exome AF: 0.0618

Gnomad OTH exome AF: 0.0548

GnomAD4 exome AF: 0.0562 AC: 82102 AN: 1461764 Hom.: 2560 Cov.: 36 AF XY: 0.0556 AC XY: 40449 AN XY: 727196

African (AFR) AF: 0.00917 AC: 307 AN: 33480

American (AMR) AF: 0.0314 AC: 1402 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0807 AC: 2110 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0251 AC: 2165 AN: 86258

European-Finnish (FIN) AF: 0.0625 AC: 3340 AN: 53398

Middle Eastern (MID) AF: 0.0570 AC: 329 AN: 5768

European-Non Finnish (NFE) AF: 0.0622 AC: 69153 AN: 1111912

Other (OTH) AF: 0.0545 AC: 3292 AN: 60394

GnomAD4 genome AF: 0.0456 AC: 6939 AN: 152278 Hom.: 202 Cov.: 32 AF XY: 0.0448 AC XY: 3339 AN XY: 74458

African (AFR) AF: 0.0117 AC: 486 AN: 41554

American (AMR) AF: 0.0581 AC: 889 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4822

European-Finnish (FIN) AF: 0.0648 AC: 688 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4248 AN: 68018

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0554 Hom.: 189

Bravo AF: 0.0443

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0624

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	-0.44
CADD	Benign	6.4
DANN	Benign	0.87
PhyloP100		0.063
Mutation Taster		=98/2	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: rs45442103; hg19: chr2-26683777; COSMIC: COSV55503150; COSMIC: COSV55503150;