chr2-26470685-CCTT-C

Variant names:

• chr2-26470685-CCTT-C
• rs368148603
• NM_194248.3:c.3928_3930delAAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_194248.3(OTOF):​c.3928_3930delAAG​(p.Lys1310del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000542 in 1,597,930 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: OTOF NM_194248.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.74
• 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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_194248.3

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.3928_3930delAAG	p.Lys1310del	conservative_inframe_deletion	Exon 32 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.1627_1629delAAG	p.Lys543del	conservative_inframe_deletion	Exon 15 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3928_3930delAAG	p.Lys1310del	conservative_inframe_deletion	Exon 32 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.3928_3930delAAG	p.Lys1310del	conservative_inframe_deletion	Exon 32 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1627_1629delAAG	p.Lys543del	conservative_inframe_deletion	Exon 15 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.1687_1689delAAG	p.Lys563del	conservative_inframe_deletion	Exon 14 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 151962 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000584 AC: 145 AN: 248192 AF XY: 0.000573

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.000651

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000552 AC: 798 AN: 1445854 Hom.: 1 AF XY: 0.000513 AC XY: 369 AN XY: 719786

African (AFR) AF: 0.000574 AC: 19 AN: 33124

American (AMR) AF: 0.000247 AC: 11 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25916

East Asian (EAS) AF: 0.000280 AC: 11 AN: 39300

South Asian (SAS) AF: 0.000338 AC: 29 AN: 85748

European-Finnish (FIN) AF: 0.000626 AC: 33 AN: 52704

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5718

European-Non Finnish (NFE) AF: 0.000602 AC: 662 AN: 1099042

Other (OTH) AF: 0.000469 AC: 28 AN: 59754

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152076 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 28 AN XY: 74334

African (AFR) AF: 0.000602 AC: 25 AN: 41506

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67968

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.000408

EpiCase AF: 0.000548

EpiControl AF: 0.000595

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=63/37	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: rs368148603; hg19: chr2-26693553; COSMIC: COSV55502292; COSMIC: COSV55502292;