3-161499249-A-G

Position:

• chr3-161499249-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080440.1(OTOL1):​c.443A>G​(p.Lys148Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OTOL1 NM_001080440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

OTOL1 (HGNC:34071): (otolin 1) This gene encodes a secreted glycoprotein with a C-terminal complement Cq1-like globular domain that belongs to the C1q/tumor necrosis factor-related protein (CTRP) family. The encoded protein is expressed in the inner ear and forms a multimeric complex called the otoconia, together with cerebellin-1 and otoconin-90, as part of the otoconial membrane. It contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Naturally occurring mutations in this gene are associated with abnormal otoconia formation and balance deficits resulting from vestibular dysfunction. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOL1	NM_001080440.1	c.443A>G	p.Lys148Arg	missense_variant	2/4	ENST00000327928.4	NP_001073909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOL1	ENST00000327928.4	c.443A>G	p.Lys148Arg	missense_variant	2/4	2	NM_001080440.1	ENSP00000330808.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447526 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.443A>G (p.K148R) alteration is located in exon 2 (coding exon 2) of the OTOL1 gene. This alteration results from a A to G substitution at nucleotide position 443, causing the lysine (K) at amino acid position 148 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Benign	0.040	D
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.40		Loss of glycosylation at K148 (P = 0.0076);
MVP		0.30
MPC		0.020
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-161217037;