2-26457897-C-T

Variant names:

• chr2-26457897-C-T
• rs549185736
• NM_194248.3:c.*341G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_194248.3(OTOF):​c.*341G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 848,142 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (15 hom.)
• Consequence: OTOF NM_194248.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.456
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00421 (640/152128) while in subpopulation NFE AF = 0.00746 (507/67992). AF 95% confidence interval is 0.00692. There are 2 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.*341G>A		3_prime_UTR_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.*143G>A		3_prime_UTR_variant	Exon 29 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.*341G>A		3_prime_UTR_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.*143G>A		3_prime_UTR_variant	Exon 29 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152010 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00488 AC: 3399 AN: 696014 Hom.: 15 Cov.: 9 AF XY: 0.00473 AC XY: 1716 AN XY: 362510

African (AFR) AF: 0.000788 AC: 14 AN: 17766

American (AMR) AF: 0.00292 AC: 83 AN: 28418

Ashkenazi Jewish (ASJ) AF: 0.000127 AC: 2 AN: 15716

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35708

South Asian (SAS) AF: 0.000305 AC: 17 AN: 55724

European-Finnish (FIN) AF: 0.00268 AC: 93 AN: 34742

Middle Eastern (MID) AF: 0.000821 AC: 2 AN: 2436

European-Non Finnish (NFE) AF: 0.00650 AC: 3062 AN: 471024

Other (OTH) AF: 0.00360 AC: 124 AN: 34480

GnomAD4 genome AF: 0.00421 AC: 640 AN: 152128 Hom.: 2 Cov.: 33 AF XY: 0.00352 AC XY: 262 AN XY: 74362

African (AFR) AF: 0.00111 AC: 46 AN: 41496

American (AMR) AF: 0.00432 AC: 66 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

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

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00746 AC: 507 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00635 Hom.: 1

Bravo AF: 0.00409

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.77
DANN	Benign	0.75
PhyloP100		-0.46
Mutation Taster		=100/0	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: rs549185736; hg19: chr2-26680765;