rs11687696

Variant names:

• chr2-26516555-T-C
• rs11687696
• NM_194248.3:c.372A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-26516555-T-C
• chr2-26516555-T-A
• chr2-26516555-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.372A>G​(p.Thr124Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,611,062 control chromosomes in the GnomAD database, including 70,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5628 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64792 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -9.09
• Publications: 16 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 2-26516555-T-C is Benign according to our data. Variant chr2-26516555-T-C is described in ClinVar as Benign. ClinVar VariationId is 21847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

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.372A>G	p.Thr124Thr	synonymous	Exon 5 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.372A>G	p.Thr124Thr	synonymous	Exon 5 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.372A>G	p.Thr124Thr	synonymous	Exon 5 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.372A>G	p.Thr124Thr	synonymous	Exon 5 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36615 AN: 151986 Hom.: 5627 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.301 AC: 75120 AN: 249402 AF XY: 0.299

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.292 AC: 425708 AN: 1458958 Hom.: 64792 Cov.: 43 AF XY: 0.291 AC XY: 211009 AN XY: 725960

African (AFR) AF: 0.0580 AC: 1943 AN: 33480

American (AMR) AF: 0.309 AC: 13831 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5308 AN: 26134

East Asian (EAS) AF: 0.467 AC: 18558 AN: 39700

South Asian (SAS) AF: 0.248 AC: 21377 AN: 86256

European-Finnish (FIN) AF: 0.401 AC: 20290 AN: 50650

Middle Eastern (MID) AF: 0.190 AC: 1095 AN: 5768

European-Non Finnish (NFE) AF: 0.293 AC: 326249 AN: 1111884

Other (OTH) AF: 0.283 AC: 17057 AN: 60366

GnomAD4 genome AF: 0.241 AC: 36638 AN: 152104 Hom.: 5628 Cov.: 32 AF XY: 0.247 AC XY: 18357 AN XY: 74346

African (AFR) AF: 0.0696 AC: 2889 AN: 41532

American (AMR) AF: 0.250 AC: 3827 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3466

East Asian (EAS) AF: 0.518 AC: 2664 AN: 5144

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4824

European-Finnish (FIN) AF: 0.412 AC: 4361 AN: 10584

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20081 AN: 67956

Other (OTH) AF: 0.223 AC: 470 AN: 2108

Alfa AF: 0.271 Hom.: 1855

Bravo AF: 0.224

Asia WGS AF: 0.432 AC: 1502 AN: 3478

EpiCase AF: 0.282

EpiControl AF: 0.277

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.013
DANN	Benign	0.26
PhyloP100		-9.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11687696; hg19: chr2-26739423; COSMIC: COSV55510690;