rs61747275

Variant names:

• chr2-26461838-G-A
• rs61747275
• NM_194248.3:c.5391C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26461838-G-A
• chr2-26461838-G-C
• chr2-26461838-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_194248.3(OTOF):​c.5391C>T​(p.Phe1797Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,154 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (36 hom., cov: 32)
  • Exomes 𝑓: 0.010 (241 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.0640
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-26461838-G-A is Benign according to our data. Variant chr2-26461838-G-A is described in ClinVar as Benign. ClinVar VariationId is 21857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.064 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0169 (2567/152266) while in subpopulation AFR AF = 0.0369 (1534/41538). AF 95% confidence interval is 0.0354. There are 36 homozygotes in GnomAd4. There are 1256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.5391C>T	p.Phe1797Phe	synonymous	Exon 43 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.3090C>T	p.Phe1030Phe	synonymous	Exon 26 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.5391C>T	p.Phe1797Phe	synonymous	Exon 43 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.5391C>T	p.Phe1797Phe	synonymous	Exon 43 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.3090C>T	p.Phe1030Phe	synonymous	Exon 26 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.3150C>T	p.Phe1050Phe	synonymous	Exon 25 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2561 AN: 152148 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00741

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0150 AC: 3760 AN: 251488 AF XY: 0.0163

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00786

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0100 AC: 14678 AN: 1461888 Hom.: 241 Cov.: 33 AF XY: 0.0112 AC XY: 8161 AN XY: 727244

African (AFR) AF: 0.0363 AC: 1216 AN: 33478

American (AMR) AF: 0.00850 AC: 380 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1097 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0427 AC: 3686 AN: 86258

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53420

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5768

European-Non Finnish (NFE) AF: 0.00637 AC: 7083 AN: 1112008

Other (OTH) AF: 0.0152 AC: 917 AN: 60396

GnomAD4 genome AF: 0.0169 AC: 2567 AN: 152266 Hom.: 36 Cov.: 32 AF XY: 0.0169 AC XY: 1256 AN XY: 74460

African (AFR) AF: 0.0369 AC: 1534 AN: 41538

American (AMR) AF: 0.0131 AC: 200 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 114 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0317 AC: 153 AN: 4834

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00741 AC: 504 AN: 68010

Other (OTH) AF: 0.0228 AC: 48 AN: 2108

Alfa AF: 0.0114 Hom.: 8

Bravo AF: 0.0186

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.5
DANN	Benign	0.80
PhyloP100		-0.064
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61747275; hg19: chr2-26684706; COSMIC: COSV55509188; COSMIC: COSV55509188;