dbSNP rs1207102900: OTOF:p.Ter1998Argext*? (chr2-26460027-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The NM_194248.3(OTOF):c.5992T>C(p.Ter1998Argext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOF
NM_194248.3 stop_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.77

Publications

1 publications found

Variant links:

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

OTOF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in NM_194248.3 Downstream stopcodon found after 341 codons.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	NM_194248.3	MANE Select	c.5992T>C	p.Ter1998Argext*?	stop_lost	Exon 46 of 47	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3	MANE Plus Clinical	c.3512+620T>C		intron	N/A	NP_919304.1	Q9HC10-2
OTOF	NM_194322.3		c.3922T>C	p.Ter1308Argext*?	stop_lost	Exon 28 of 29	NP_919303.1	Q9HC10-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5992T>C	p.Ter1998Argext*?	stop_lost	Exon 46 of 47	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000402415.8	TSL:1	c.3751T>C	p.Ter1251Argext*?	stop_lost	Exon 28 of 29	ENSP00000383906.4	A0A2U3TZT7
OTOF	ENST00000338581.10	TSL:1	c.3691T>C	p.Ter1231Argext*?	stop_lost	Exon 29 of 30	ENSP00000345137.6	Q9HC10-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

179252

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1414644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698910

African (AFR)

AF:

0.00

AC:

AN:

32732

American (AMR)

AF:

0.00

AC:

AN:

36660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

37792

South Asian (SAS)

AF:

0.00

AC:

AN:

80268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4998

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087860

Other (OTH)

AF:

0.00

AC:

AN:

58770

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.74

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

PhyloP100

6.8

Vest4

0.36

GERP RS

2.2

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over