rs55639868

Variant names:

• chr2-26502290-G-A
• rs55639868
• NM_194248.3:c.710+10C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.710+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,840 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (87 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -1.39
• Publications: 5 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-26502290-G-A is Benign according to our data. Variant chr2-26502290-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48273.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00884 (1347/152306) while in subpopulation NFE AF = 0.0136 (928/68018). AF 95% confidence interval is 0.0129. There are 7 homozygotes in GnomAd4. There are 634 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR 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.710+10C>T		intron	N/A	NP_919224.1
	OTOF	NM_001287489.2		c.710+10C>T		intron	N/A	NP_001274418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.710+10C>T		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000403946.7	TSL:5	c.710+10C>T		intron	N/A	ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1348 AN: 152188 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00999 AC: 2506 AN: 250932 AF XY: 0.0102

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00943

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00303

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0102 AC: 14939 AN: 1461534 Hom.: 87 Cov.: 32 AF XY: 0.0104 AC XY: 7528 AN XY: 727076

African (AFR) AF: 0.00143 AC: 48 AN: 33472

American (AMR) AF: 0.0103 AC: 459 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 690 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00435 AC: 375 AN: 86232

European-Finnish (FIN) AF: 0.00396 AC: 211 AN: 53314

Middle Eastern (MID) AF: 0.0140 AC: 80 AN: 5708

European-Non Finnish (NFE) AF: 0.0111 AC: 12374 AN: 1111890

Other (OTH) AF: 0.0116 AC: 702 AN: 60378

GnomAD4 genome AF: 0.00884 AC: 1347 AN: 152306 Hom.: 7 Cov.: 33 AF XY: 0.00851 AC XY: 634 AN XY: 74464

African (AFR) AF: 0.00166 AC: 69 AN: 41560

American (AMR) AF: 0.00961 AC: 147 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 928 AN: 68018

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00842

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.9
DANN	Benign	0.59
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs55639868; hg19: chr2-26725158;