rs199567872

chr2-26466857-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_194248.3(OTOF):c.4363-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: OTOF NM_194248.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001639
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.22

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26466857-C-T is Benign according to our data. Variant chr2-26466857-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505368.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4363-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000272371.7
OTOF	NM_194323.3	c.2062-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4363-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2062-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251408 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135890

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000752 AC: 110 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 25, 2016

The c.4363-6G>A variant in OTOF has not been previously reported in individuals with hearing loss, but has been identified in 4/11568 Latino and 4/66578 Europea n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs199567872). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Th is variant is located in the 3' splice region. Computational tools do not sugges t an impact to splicing. However, this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the c.4363-6G>A variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.1
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0080
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

Publications

LitVar

Other links and lift over

dbSNP: rs199567872; hg19: chr2-26689725;