rs80356570

Variant names:

• chr2-26477231-G-A
• rs80356570
• NM_194248.3:c.2464C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26477231-G-A
• chr2-26477231-G-C
• chr2-26477231-G-T

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.2464C>T​(p.Arg822Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,609,140 control chromosomes in the GnomAD database, including 374 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. R822Q) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 32)
  • Exomes 𝑓: 0.019 (354 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 2.12
• 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, 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

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008108318).
• BP6: Variant 2-26477231-G-A is Benign according to our data. Variant chr2-26477231-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2230/152286) while in subpopulation NFE AF = 0.0195 (1325/68000). AF 95% confidence interval is 0.0186. There are 20 homozygotes in GnomAd4. There are 1020 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,Unknown 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.2464C>T	p.Arg822Trp	missense	Exon 21 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.223C>T	p.Arg75Trp	missense	Exon 4 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2464C>T	p.Arg822Trp	missense	Exon 21 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.2464C>T	p.Arg822Trp	missense	Exon 21 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.223C>T	p.Arg75Trp	missense	Exon 4 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.223C>T	p.Arg75Trp	missense	Exon 3 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2228 AN: 152170 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00890

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0144 AC: 3473 AN: 241134 AF XY: 0.0147

Gnomad AFR exome AF: 0.00924

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0195 AC: 28407 AN: 1456854 Hom.: 354 Cov.: 33 AF XY: 0.0189 AC XY: 13727 AN XY: 724436

African (AFR) AF: 0.00834 AC: 279 AN: 33460

American (AMR) AF: 0.00790 AC: 351 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 532 AN: 26038

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39640

South Asian (SAS) AF: 0.00323 AC: 276 AN: 85512

European-Finnish (FIN) AF: 0.0227 AC: 1153 AN: 50832

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5756

European-Non Finnish (NFE) AF: 0.0223 AC: 24733 AN: 1110972

Other (OTH) AF: 0.0169 AC: 1020 AN: 60232

GnomAD4 genome AF: 0.0146 AC: 2230 AN: 152286 Hom.: 20 Cov.: 32 AF XY: 0.0137 AC XY: 1020 AN XY: 74476

African (AFR) AF: 0.00895 AC: 372 AN: 41574

American (AMR) AF: 0.0123 AC: 189 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1325 AN: 68000

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0178 Hom.: 77

Bravo AF: 0.0143

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00985 AC: 43

ESP6500EA AF: 0.0231 AC: 198

ExAC AF: 0.0141 AC: 1699

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	3	Autosomal recessive nonsyndromic hearing loss 9 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.47
MPC		0.59
ClinPred		0.037	T
GERP RS		2.9
Varity_R		0.43
gMVP		0.55
Mutation Taster		=92/8	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: rs80356570; hg19: chr2-26700099; COSMIC: COSV55516101; COSMIC: COSV55516101;