chr2-26477025-C-T

Variant names:

• chr2-26477025-C-T
• rs147865867
• NM_194248.3:c.2542G>A

Variant summary

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

The NM_194248.3(OTOF):​c.2542G>A​(p.Asp848Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,433,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2542G>A	p.Asp848Asn	missense_variant	Exon 22 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.301G>A	p.Asp101Asn	missense_variant	Exon 5 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2542G>A	p.Asp848Asn	missense_variant	Exon 22 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.301G>A	p.Asp101Asn	missense_variant	Exon 5 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.000129 AC: 19 AN: 147396 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000448 AC: 10 AN: 223226 AF XY: 0.0000330

Gnomad AFR exome AF: 0.000714

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 AF: 0.0000140 AC: 18 AN: 1285788 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 8 AN XY: 643578

Gnomad4 AFR exome AF: 0.000267 AC: 8 AN: 29960

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 41710

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 23920

Gnomad4 EAS exome AF: 0.0000555 AC: 2 AN: 36026

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 81514

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 45810

Gnomad4 NFE exome AF: 0.00000413 AC: 4 AN: 968000

Gnomad4 Remaining exome AF: 0.0000747 AC: 4 AN: 53568

GnomAD4 genome AF: 0.000115 AC: 17 AN: 147528 Hom.: 0 Cov.: 31 AF XY: 0.0000973 AC XY: 7 AN XY: 71934

Gnomad4 AFR AF: 0.000421 AC: 0.000420688 AN: 0.000420688

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000446 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000688 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000666 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp848Asn has been previously reported in 2 individuals with hearing loss, 1 of whom also had a second missense variant in OTOF (Sloan-Heggen 2016, LMM un published data). This variant has also been identified in 0.1% (8/6858) of Afric an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs147865867); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest the variant may impact the protein, though this information is not pred ictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp848Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;.;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;D;.
Polyphen		0.99	D;D;.;D;.;D
Vest4		0.80
MVP		0.92
MPC		0.56
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.86
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs147865867; hg19: chr2-26699893;