2-26480866-C-T

Variant names:

• chr2-26480866-C-T
• rs55676840
• NM_194248.3:c.1723G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA142762/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 33)
  • Exomes 𝑓: 0.012 (177 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign reviewed by expert panel B:9 O:1
• Conservation: PhyloP100: 5.00
• 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, 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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1723G>A	p.Val575Met	missense	Exon 15 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.1723G>A	p.Val575Met	missense	Exon 15 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.1723G>A	p.Val575Met	missense	Exon 15 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.1723G>A	p.Val575Met	missense	Exon 15 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1350 AN: 152164 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0121 AC: 3025 AN: 249328 AF XY: 0.0134

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00944

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0123 AC: 18023 AN: 1460734 Hom.: 177 Cov.: 33 AF XY: 0.0131 AC XY: 9526 AN XY: 726646

African (AFR) AF: 0.00191 AC: 64 AN: 33480

American (AMR) AF: 0.00304 AC: 136 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

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

South Asian (SAS) AF: 0.0378 AC: 3257 AN: 86256

European-Finnish (FIN) AF: 0.0107 AC: 560 AN: 52300

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0119 AC: 13241 AN: 1111994

Other (OTH) AF: 0.0116 AC: 700 AN: 60382

GnomAD4 genome AF: 0.00886 AC: 1349 AN: 152282 Hom.: 17 Cov.: 33 AF XY: 0.00917 AC XY: 683 AN XY: 74456

African (AFR) AF: 0.00236 AC: 98 AN: 41564

American (AMR) AF: 0.00379 AC: 58 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0433 AC: 209 AN: 4824

European-Finnish (FIN) AF: 0.00847 AC: 90 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 832 AN: 67998

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.0104 Hom.: 24

Bravo AF: 0.00778

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0130 AC: 1577

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00972

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (2)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T
Sift4G	Benign	0.13	T
Polyphen		0.80	P
Vest4		0.45
MPC		0.26
ClinPred		0.077	T
GERP RS		4.5
Varity_R		0.26
gMVP		0.76
Mutation Taster		=93/7	polymorphism (auto)

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: rs55676840; hg19: chr2-26703734; COSMIC: COSV55506444; COSMIC: COSV55506444;