rs1482726409

Variant names:

• chr2-26458102-T-A
• rs1482726409
• NM_194323.3:c.3631A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26458102-T-A
• chr2-26458102-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194323.3(OTOF):​c.3631A>T​(p.Met1211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1211V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194323.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16979629).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194323.3. 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_194323.3	MANE Plus Clinical	c.3631A>T	p.Met1211Leu	missense	Exon 29 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_194248.3	MANE Select	c.*136A>T		3_prime_UTR	Exon 47 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.5932A>T	p.Met1978Leu	missense	Exon 46 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.3631A>T	p.Met1211Leu	missense	Exon 29 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.*136A>T		3_prime_UTR	Exon 47 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000402415.8	TSL:1	c.*136A>T		3_prime_UTR	Exon 29 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.86
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
PhyloP100		1.6
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.40
MutPred		0.34		Loss of MoRF binding (P = 0.3379)
MVP		0.70
ClinPred		0.26	T
GERP RS		3.6
Mutation Taster		=73/27	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: rs1482726409; hg19: chr2-26680970;