rs111033427

Variant names:

• chr2-26477768-G-C
• rs111033427
• ENST00000402415.8:c.-46C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000402415.8(OTOF):​c.-46C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,612,286 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (33 hom.)
• Consequence: OTOF ENST00000402415.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.408
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26477768-G-C is Benign according to our data. Variant chr2-26477768-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00433 (659/152258) while in subpopulation AMR AF = 0.00804 (123/15294). AF 95% confidence interval is 0.00689. There are 1 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402415.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2215-19C>G		intron	N/A	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.-27-19C>G		intron	N/A	NP_919304.1
	OTOF	NM_194322.3		c.126C>G	p.Thr42Thr	synonymous	Exon 1 of 29	NP_919303.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000402415.8	TSL:1	c.-46C>G		5_prime_UTR	Exon 1 of 29	ENSP00000383906.4
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2215-19C>G		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-27-19C>G		intron	N/A	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00437 AC: 1084 AN: 248176 AF XY: 0.00449

Gnomad AFR exome AF: 0.000883

Gnomad AMR exome AF: 0.00706

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00536 AC: 7825 AN: 1460028 Hom.: 33 Cov.: 34 AF XY: 0.00529 AC XY: 3841 AN XY: 726292

African (AFR) AF: 0.000866 AC: 29 AN: 33468

American (AMR) AF: 0.00689 AC: 308 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000731 AC: 63 AN: 86198

European-Finnish (FIN) AF: 0.00275 AC: 143 AN: 52044

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00623 AC: 6931 AN: 1111758

Other (OTH) AF: 0.00459 AC: 277 AN: 60340

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74428

African (AFR) AF: 0.00103 AC: 43 AN: 41548

American (AMR) AF: 0.00804 AC: 123 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00513 Hom.: 0

Bravo AF: 0.00438

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00749

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.45
PhyloP100		-0.41
PromoterAI		0.062	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033427; hg19: chr2-26700636;