2-26480949-G-T

Variant names:

• chr2-26480949-G-T
• rs200191563
• NM_194248.3:c.1640C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_194248.3(OTOF):​c.1640C>A​(p.Thr547Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T547M) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• Publications: 7 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

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.1640C>A	p.Thr547Lys	missense	Exon 15 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.1640C>A	p.Thr547Lys	missense	Exon 15 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.1640C>A	p.Thr547Lys	missense	Exon 15 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.1640C>A	p.Thr547Lys	missense	Exon 15 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249768 AF XY: 0.00000738

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460722 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 726642

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52284

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.0085	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.79
MutPred		0.54		Gain of ubiquitination at T547 (P = 0.0177)
MVP		0.93
MPC		0.49
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.79
Mutation Taster		=29/71	disease causing

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: rs200191563; hg19: chr2-26703817; COSMIC: COSV99718323; COSMIC: COSV99718323;