rs41288779

Variant names:

• chr2-26489693-C-T
• rs41288779
• NM_194248.3:c.945G>A

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.945G>A​(p.Lys315Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,612,408 control chromosomes in the GnomAD database, including 3,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (481 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3372 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.0250
• 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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-26489693-C-T is Benign according to our data. Variant chr2-26489693-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 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.945G>A	p.Lys315Lys	synonymous	Exon 10 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.945G>A	p.Lys315Lys	synonymous	Exon 10 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.945G>A	p.Lys315Lys	synonymous	Exon 10 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.945G>A	p.Lys315Lys	synonymous	Exon 10 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10849 AN: 152202 Hom.: 481 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0465

GnomAD2 exomes AF: 0.0539 AC: 13512 AN: 250800 AF XY: 0.0525

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0546

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0376

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0652 AC: 95135 AN: 1460088 Hom.: 3372 Cov.: 31 AF XY: 0.0641 AC XY: 46557 AN XY: 726374

African (AFR) AF: 0.116 AC: 3868 AN: 33462

American (AMR) AF: 0.0434 AC: 1943 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1453 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0397 AC: 3428 AN: 86244

European-Finnish (FIN) AF: 0.0395 AC: 2071 AN: 52370

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.0709 AC: 78785 AN: 1111328

Other (OTH) AF: 0.0573 AC: 3457 AN: 60366

GnomAD4 genome AF: 0.0713 AC: 10853 AN: 152320 Hom.: 481 Cov.: 33 AF XY: 0.0681 AC XY: 5073 AN XY: 74478

African (AFR) AF: 0.114 AC: 4732 AN: 41558

American (AMR) AF: 0.0433 AC: 663 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4830

European-Finnish (FIN) AF: 0.0357 AC: 380 AN: 10630

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4515 AN: 68018

Other (OTH) AF: 0.0460 AC: 97 AN: 2110

Alfa AF: 0.0758 Hom.: 446

Bravo AF: 0.0737

Asia WGS AF: 0.0260 AC: 90 AN: 3478

EpiCase AF: 0.0586

EpiControl AF: 0.0600

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.9
DANN	Benign	0.59
PhyloP100		-0.025
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41288779; hg19: chr2-26712561; COSMIC: COSV108092256;