NM_017433.5:c.1643C>A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_017433.5(MYO3A):c.1643C>A(p.Pro548His) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,613,648 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017433.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO3A | ENST00000642920.2 | c.1643C>A | p.Pro548His | missense_variant | Exon 16 of 35 | NM_017433.5 | ENSP00000495965.1 | |||
MYO3A | ENST00000543632.5 | c.1643C>A | p.Pro548His | missense_variant | Exon 15 of 17 | 1 | ENSP00000445909.1 | |||
MYO3A | ENST00000642197.1 | n.1847C>A | non_coding_transcript_exon_variant | Exon 16 of 27 | ||||||
MYO3A | ENST00000647478.1 | n.1643C>A | non_coding_transcript_exon_variant | Exon 15 of 30 | ENSP00000493932.1 |
Frequencies
GnomAD3 genomes AF: 0.00120 AC: 183AN: 152108Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000419 AC: 105AN: 250834Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135802
GnomAD4 exome AF: 0.000222 AC: 324AN: 1461422Hom.: 1 Cov.: 31 AF XY: 0.000212 AC XY: 154AN XY: 727018
GnomAD4 genome AF: 0.00122 AC: 185AN: 152226Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 83AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
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The p.Pro548His variant (rs143918373) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.4 percent in the African population (identified on 95 out of 24,022 chromosomes) and has been reported to the ClinVar database (Variation ID: 178465). The proline at position 548 is highly conserved up to frog considering 11 species (Alamut v2.10) and computational analyses of the effects of the p.Pro548His variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro548His variant with certainty. -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1
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. -
Inborn genetic diseases Uncertain:1
The c.1643C>A (p.P548H) alteration is located in exon 16 (coding exon 14) of the MYO3A gene. This alteration results from a C to A substitution at nucleotide position 1643, causing the proline (P) at amino acid position 548 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Pro548His in Exon 16 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (15/3732) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs143918373). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at