rs41288773

Variant names:

• chr2-26472632-A-C
• rs41288773
• NM_194248.3:c.3751T>G

Variant summary

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

The NM_194248.3(OTOF):​c.3751T>G​(p.Cys1251Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,122 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 33)
  • Exomes 𝑓: 0.022 (384 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.62
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041293204).
• BP6: Variant 2-26472632-A-C is Benign according to our data. Variant chr2-26472632-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0152 (2317/152342) while in subpopulation NFE AF = 0.0241 (1642/68032). AF 95% confidence interval is 0.0232. There are 19 homozygotes in GnomAd4. There are 1046 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.3751T>G	p.Cys1251Gly	missense	Exon 30 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.1493-43T>G		intron	N/A	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3751T>G	p.Cys1251Gly	missense	Exon 30 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.3751T>G	p.Cys1251Gly	missense	Exon 30 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000402415.8	TSL:1	c.1510T>G	p.Cys504Gly	missense	Exon 12 of 29	ENSP00000383906.4	A0A2U3TZT7
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1493-43T>G		intron	N/A	ENSP00000344521.3	Q9HC10-2

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2319 AN: 152224 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0157 AC: 3927 AN: 249600 AF XY: 0.0164

Gnomad AFR exome AF: 0.00342

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00600

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0217 AC: 31685 AN: 1460780 Hom.: 384 Cov.: 32 AF XY: 0.0213 AC XY: 15512 AN XY: 726668

African (AFR) AF: 0.00355 AC: 119 AN: 33478

American (AMR) AF: 0.0111 AC: 495 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00691 AC: 596 AN: 86238

European-Finnish (FIN) AF: 0.0176 AC: 928 AN: 52582

Middle Eastern (MID) AF: 0.0272 AC: 157 AN: 5768

European-Non Finnish (NFE) AF: 0.0252 AC: 28068 AN: 1111828

Other (OTH) AF: 0.0195 AC: 1177 AN: 60372

GnomAD4 genome AF: 0.0152 AC: 2317 AN: 152342 Hom.: 19 Cov.: 33 AF XY: 0.0140 AC XY: 1046 AN XY: 74498

African (AFR) AF: 0.00476 AC: 198 AN: 41584

American (AMR) AF: 0.0144 AC: 221 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1642 AN: 68032

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0203 Hom.: 94

Bravo AF: 0.0147

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0198 AC: 170

ExAC AF: 0.0166 AC: 2013

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0238

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.8
DANN	Benign	0.50
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.21
Sift	Benign	0.39	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.19
ClinPred		0.0030	T
GERP RS		-4.8
Varity_R		0.045
gMVP		0.44
Mutation Taster		=99/1	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: rs41288773; hg19: chr2-26695500;