NM_016239.4:c.215G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_016239.4(MYO15A):c.215G>A(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R72R) has been classified as Likely benign.
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 3Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
- nonsyndromic genetic hearing lossInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000327 AC: 8AN: 244784 AF XY: 0.0000149 show subpopulations
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460350Hom.: 0 Cov.: 35 AF XY: 0.00000551 AC XY: 4AN XY: 726476 show subpopulations
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74342 show subpopulations
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Arg72His variant in MYO15A has not been previously reported in individuals with hearing loss, but has been identified in 11/34300 Latino chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP r s759523877). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predic tion tools do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Arg72His variant is uncertain. -
Inborn genetic diseases Uncertain:1
The c.215G>A (p.R72H) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 215, causing the arginine (R) at amino acid position 72 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the MYO15A protein (p.Arg72His). This variant is present in population databases (rs759523877, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 517275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO15A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at