rs921891243

Variant names:

• chr2-26476009-T-C
• rs921891243
• NM_194248.3:c.2896A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-26476009-T-C
• chr2-26476009-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_194248.3(OTOF):​c.2896A>G​(p.Met966Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03
• 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, 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

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_194248.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26640353).

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.2896A>G	p.Met966Val	missense	Exon 24 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.655A>G	p.Met219Val	missense	Exon 7 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2896A>G	p.Met966Val	missense	Exon 24 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.2896A>G	p.Met966Val	missense	Exon 24 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.655A>G	p.Met219Val	missense	Exon 7 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.655A>G	p.Met219Val	missense	Exon 6 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460456 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.94	N
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.032	B
Vest4		0.79
MutPred		0.49		Loss of MoRF binding (P = 0.1284)
MVP		0.77
MPC		0.40
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.34
gMVP		0.46
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs921891243; hg19: chr2-26698877;