rs28937591

Positions:

• chr2-26461756-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_194248.3(OTOF):​c.5473C>G​(p.Pro1825Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 2-26461756-G-C is Pathogenic according to our data. Variant chr2-26461756-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6138.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5473C>G	p.Pro1825Ala	missense_variant	43/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3172C>G	p.Pro1058Ala	missense_variant	26/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5473C>G	p.Pro1825Ala	missense_variant	43/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3172C>G	p.Pro1058Ala	missense_variant	26/29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;.;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.8	.;.;.;M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.;D;D;.
Sift4G	Uncertain	0.0050	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.89
MutPred		0.79		.;.;.;Loss of methylation at K1823 (P = 0.0832);Loss of methylation at K1823 (P = 0.0832);.;
MVP		0.93
MPC		0.65
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937591; hg19: chr2-26684624;