rs76130130

Variant names:

• chr2-26477826-A-C
• rs76130130
• ENST00000402415.8:c.-104T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000402415.8(OTOF):​c.-104T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,587,232 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: OTOF ENST00000402415.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.168
• 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 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004008025).
• BP6: Variant 2-26477826-A-C is Benign according to our data. Variant chr2-26477826-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48190.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 = 0.00341 (519/152214) while in subpopulation NFE AF = 0.00487 (331/67992). AF 95% confidence interval is 0.00444. There are 1 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402415.8. 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.2215-77T>G		intron	N/A	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.-28+18T>G		intron	N/A	NP_919304.1
	OTOF	NM_194322.3		c.68T>G	p.Ile23Ser	missense	Exon 1 of 29	NP_919303.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000402415.8	TSL:1	c.-104T>G		5_prime_UTR	Exon 1 of 29	ENSP00000383906.4
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2215-77T>G		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-28+18T>G		intron	N/A	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.00430 AC: 866 AN: 201304 AF XY: 0.00414

Gnomad AFR exome AF: 0.000663

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000207

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00708

GnomAD4 exome AF: 0.00535 AC: 7682 AN: 1435018 Hom.: 36 Cov.: 34 AF XY: 0.00517 AC XY: 3677 AN XY: 711602

African (AFR) AF: 0.000854 AC: 28 AN: 32786

American (AMR) AF: 0.00537 AC: 217 AN: 40436

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 401 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 38092

South Asian (SAS) AF: 0.000805 AC: 67 AN: 83252

European-Finnish (FIN) AF: 0.000257 AC: 13 AN: 50642

Middle Eastern (MID) AF: 0.00470 AC: 27 AN: 5742

European-Non Finnish (NFE) AF: 0.00602 AC: 6621 AN: 1098964

Other (OTH) AF: 0.00518 AC: 308 AN: 59480

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74424

African (AFR) AF: 0.00120 AC: 50 AN: 41548

American (AMR) AF: 0.00353 AC: 54 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 67992

Other (OTH) AF: 0.00808 AC: 17 AN: 2104

Alfa AF: 0.00484 Hom.: 6

Bravo AF: 0.00395

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 3

ESP6500EA AF: 0.00542 AC: 25

ExAC AF: 0.00362 AC: 430

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.0
DANN	Benign	0.94
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.17
Polyphen		0.0010	B
ClinPred		0.060	T
GERP RS		-4.5
PromoterAI		0.0074	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76130130; hg19: chr2-26700694;