rs139767460

Variant names:

• chr2-26464041-G-A
• rs139767460
• NM_194248.3:c.5026C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26464041-G-A
• chr2-26464041-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.5026C>T​(p.Arg1676Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,613,656 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1676H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (18 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.03
• Publications: 15 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008848131).
• BP6: Variant 2-26464041-G-A is Benign according to our data. Variant chr2-26464041-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00086 (131/152282) while in subpopulation EAS AF = 0.0195 (101/5168). AF 95% confidence interval is 0.0165. There are 4 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.5026C>T	p.Arg1676Cys	missense	Exon 40 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2725C>T	p.Arg909Cys	missense	Exon 23 of 29	NP_919304.1
	OTOF	NM_001287489.2		c.5026C>T	p.Arg1676Cys	missense	Exon 40 of 46	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5026C>T	p.Arg1676Cys	missense	Exon 40 of 47	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2725C>T	p.Arg909Cys	missense	Exon 23 of 29	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.2785C>T	p.Arg929Cys	missense	Exon 22 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00144 AC: 362 AN: 250878 AF XY: 0.00137

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000832 AC: 1216 AN: 1461374 Hom.: 18 Cov.: 32 AF XY: 0.000799 AC XY: 581 AN XY: 727004

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0272 AC: 1078 AN: 39696

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52948

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111984

Other (OTH) AF: 0.000729 AC: 44 AN: 60390

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74462

African (AFR) AF: 0.000553 AC: 23 AN: 41564

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000727 Hom.: 3

Bravo AF: 0.000979

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00134 AC: 163

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.97	D
Vest4		0.47
MVP		0.74
MPC		0.55
ClinPred		0.061	T
GERP RS		3.5
Varity_R		0.21
gMVP		0.68
Mutation Taster		=91/9	polymorphism

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: rs139767460; hg19: chr2-26686909; COSMIC: COSV55502099;