rs4665855

Variant names:

• chr2-26477832-G-A
• rs4665855
• ENST00000402415.8:c.-110C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194322.3(OTOF):​c.62C>T​(p.Pro21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,576,720 control chromosomes in the GnomAD database, including 163,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18095 hom., cov: 32)
  • Exomes 𝑓: 0.44 (145627 hom.)
• Consequence: OTOF NM_194322.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.327
• Publications: 27 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• 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 (MetaRNN=1.2123064E-6).
• BP6: Variant 2-26477832-G-A is Benign according to our data. Variant chr2-26477832-G-A is described in ClinVar as Benign. ClinVar VariationId is 48191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194322.3. 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.2215-83C>T		intron	N/A	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.-28+12C>T		intron	N/A	NP_919304.1	Q9HC10-2
	OTOF	NM_194322.3		c.62C>T	p.Pro21Leu	missense	Exon 1 of 29	NP_919303.1	Q9HC10-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000402415.8	TSL:1	c.-110C>T		5_prime_UTR	Exon 1 of 29	ENSP00000383906.4	A0A2U3TZT7
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2215-83C>T		intron	N/A	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-28+12C>T		intron	N/A	ENSP00000344521.3	Q9HC10-2

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71619 AN: 151918 Hom.: 18076 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.440

GnomAD2 exomes AF: 0.524 AC: 101448 AN: 193584 AF XY: 0.516

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.987

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.438 AC: 623898 AN: 1424682 Hom.: 145627 Cov.: 38 AF XY: 0.440 AC XY: 310290 AN XY: 705488

African (AFR) AF: 0.447 AC: 14538 AN: 32522

American (AMR) AF: 0.670 AC: 26004 AN: 38828

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9039 AN: 25490

East Asian (EAS) AF: 0.976 AC: 36580 AN: 37462

South Asian (SAS) AF: 0.540 AC: 44431 AN: 82338

European-Finnish (FIN) AF: 0.564 AC: 28191 AN: 50028

Middle Eastern (MID) AF: 0.354 AC: 2027 AN: 5730

European-Non Finnish (NFE) AF: 0.399 AC: 435841 AN: 1093212

Other (OTH) AF: 0.461 AC: 27247 AN: 59072

GnomAD4 genome AF: 0.471 AC: 71682 AN: 152038 Hom.: 18095 Cov.: 32 AF XY: 0.484 AC XY: 35978 AN XY: 74320

African (AFR) AF: 0.453 AC: 18789 AN: 41480

American (AMR) AF: 0.574 AC: 8769 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1246 AN: 3470

East Asian (EAS) AF: 0.984 AC: 5086 AN: 5170

South Asian (SAS) AF: 0.564 AC: 2713 AN: 4814

European-Finnish (FIN) AF: 0.594 AC: 6264 AN: 10550

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27287 AN: 67956

Other (OTH) AF: 0.445 AC: 938 AN: 2106

Alfa AF: 0.426 Hom.: 21793

Bravo AF: 0.471

TwinsUK AF: 0.382 AC: 1415

ALSPAC AF: 0.405 AC: 1560

ESP6500AA AF: 0.440 AC: 1167

ESP6500EA AF: 0.394 AC: 1821

ExAC AF: 0.472 AC: 55243

Asia WGS AF: 0.746 AC: 2589 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.0
DANN	Benign	0.65
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.33
Polyphen		0.0	B
ClinPred		0.025	T
GERP RS		-0.57
PromoterAI		-0.017	Neutral
Mutation Taster		=96/4	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: rs4665855; hg19: chr2-26700700; COSMIC: COSV55522507; COSMIC: COSV55522507;