rs397517940

chr2-26475933-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_194248.3(OTOF):c.2972A>G(p.Asn991Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,609,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12352306).
• BP6: Variant 2-26475933-T-C is Benign according to our data. Variant chr2-26475933-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48211.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2972A>G	p.Asn991Ser	missense_variant	24/47	ENST00000272371.7
OTOF	NM_194323.3	c.731A>G	p.Asn244Ser	missense_variant	7/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2972A>G	p.Asn991Ser	missense_variant	24/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.731A>G	p.Asn244Ser	missense_variant	7/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000492 AC: 12 AN: 243862 Hom.: 0 AF XY: 0.0000378 AC XY: 5 AN XY: 132404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000672

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1457800 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 724894

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.2972A>G (p.N991S) alteration is located in exon 24 (coding exon 24) of the OTOF gene. This alteration results from a A to G substitution at nucleotide position 2972, causing the asparagine (N) at amino acid position 991 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 07, 2011

Asn991Ser in exon 24 of OTOF: This variant is not expected to have clinical sign ificance because computational analyses (PolyPhen, SIFT, AlignGVGD) do not sugge st a high likelihood of clinical significance primarily based upon a lack of con servation across species including mammals. Of note, chicken has a serine at thi s position despite high nearby amino acid conservation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Benign	0.93
Eigen	Benign	-0.24
Eigen_PC	Benign	0.000092
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.96	D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.26	N;N;.;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.79	T;T;.;T;T;.
Sift4G	Benign	0.84	T;T;.;T;T;.
Polyphen		0.0	B;B;.;B;.;B
Vest4		0.15
MutPred		0.43		.;.;.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.75
MPC		0.12
ClinPred		0.10	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.051

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517940; hg19: chr2-26698801;