2-26474554-C-G

Variant names:

• chr2-26474554-C-G
• rs80356574
• NM_194248.3:c.3247G>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.3247G>C​(p.Ala1083Pro) 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 1,612,842 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1083T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 31)
  • Exomes 𝑓: 0.019 (354 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.494
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005121857).
• BP6: Variant 2-26474554-C-G is Benign according to our data. Variant chr2-26474554-C-G is described in ClinVar as Benign. ClinVar VariationId is 21844.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 = 0.0147 (2245/152340) while in subpopulation NFE AF = 0.0195 (1329/68028). AF 95% confidence interval is 0.0187. There are 20 homozygotes in GnomAd4. There are 1020 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.3247G>C	p.Ala1083Pro	missense	Exon 26 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.1006G>C	p.Ala336Pro	missense	Exon 9 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.3247G>C	p.Ala1083Pro	missense	Exon 26 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.3247G>C	p.Ala1083Pro	missense	Exon 26 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.1006G>C	p.Ala336Pro	missense	Exon 9 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.1006G>C	p.Ala336Pro	missense	Exon 8 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2243 AN: 152222 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00921

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0145 AC: 3606 AN: 249378 AF XY: 0.0147

Gnomad AFR exome AF: 0.00949

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0195 AC: 28469 AN: 1460502 Hom.: 354 Cov.: 33 AF XY: 0.0190 AC XY: 13770 AN XY: 726540

African (AFR) AF: 0.00884 AC: 296 AN: 33470

American (AMR) AF: 0.00786 AC: 351 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 538 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00321 AC: 277 AN: 86226

European-Finnish (FIN) AF: 0.0228 AC: 1191 AN: 52338

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5766

European-Non Finnish (NFE) AF: 0.0222 AC: 24738 AN: 1111832

Other (OTH) AF: 0.0168 AC: 1016 AN: 60372

GnomAD4 genome AF: 0.0147 AC: 2245 AN: 152340 Hom.: 20 Cov.: 31 AF XY: 0.0137 AC XY: 1020 AN XY: 74486

African (AFR) AF: 0.00926 AC: 385 AN: 41580

American (AMR) AF: 0.0123 AC: 189 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0195 AC: 1329 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00863 Hom.: 1

Bravo AF: 0.0143

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0233 AC: 200

ExAC AF: 0.0143 AC: 1735

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0210

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.49
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.045
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.28	B
Vest4		0.29
MPC		0.31
ClinPred		0.0060	T
GERP RS		4.9
Varity_R		0.25
gMVP		0.62
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80356574; hg19: chr2-26697422; COSMIC: COSV55516027; COSMIC: COSV55516027;