rs2272071

Variant names:

• chr2-26465794-C-T
• rs2272071
• NM_194248.3:c.4677G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000272371.7(OTOF):​c.4677G>A​(p.Val1559Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,614,194 control chromosomes in the GnomAD database, including 1,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 33)
  • Exomes 𝑓: 0.022 (843 hom.)
• Consequence: OTOF ENST00000272371.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.230
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-26465794-C-T is Benign according to our data. Variant chr2-26465794-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000272371.7. 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.4677G>A	p.Val1559Val	synonymous	Exon 38 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2376G>A	p.Val792Val	synonymous	Exon 21 of 29	NP_919304.1
	OTOF	NM_001287489.2		c.4677G>A	p.Val1559Val	synonymous	Exon 38 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.4677G>A	p.Val1559Val	synonymous	Exon 38 of 47	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2376G>A	p.Val792Val	synonymous	Exon 21 of 29	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.2436G>A	p.Val812Val	synonymous	Exon 20 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6025 AN: 152182 Hom.: 179 Cov.: 33

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0347 AC: 8737 AN: 251444 AF XY: 0.0337

Gnomad AFR exome AF: 0.0686

Gnomad AMR exome AF: 0.0364

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0218 AC: 31847 AN: 1461894 Hom.: 843 Cov.: 32 AF XY: 0.0223 AC XY: 16188 AN XY: 727248

African (AFR) AF: 0.0706 AC: 2364 AN: 33480

American (AMR) AF: 0.0380 AC: 1700 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26136

East Asian (EAS) AF: 0.140 AC: 5551 AN: 39700

South Asian (SAS) AF: 0.0447 AC: 3857 AN: 86258

European-Finnish (FIN) AF: 0.0346 AC: 1847 AN: 53420

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14585 AN: 1112012

Other (OTH) AF: 0.0298 AC: 1799 AN: 60396

GnomAD4 genome AF: 0.0396 AC: 6034 AN: 152300 Hom.: 180 Cov.: 33 AF XY: 0.0411 AC XY: 3060 AN XY: 74470

African (AFR) AF: 0.0695 AC: 2888 AN: 41552

American (AMR) AF: 0.0388 AC: 594 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.138 AC: 714 AN: 5160

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4832

European-Finnish (FIN) AF: 0.0420 AC: 446 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 938 AN: 68040

Other (OTH) AF: 0.0336 AC: 71 AN: 2114

Alfa AF: 0.0198 Hom.: 123

Bravo AF: 0.0408

Asia WGS AF: 0.0980 AC: 341 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0132

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		0.23
Mutation Taster		=100/0	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: rs2272071; hg19: chr2-26688662; COSMIC: COSV55498931;