19-50252726-C-T
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001145809.2(MYH14):c.1918C>T(p.Arg640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,595,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R640G) has been classified as Likely benign.
Frequency
Consequence
NM_001145809.2 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant nonsyndromic hearing loss 4AInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
- peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- nonsyndromic genetic hearing lossInheritance: AD Classification: MODERATE Submitted by: ClinGen
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH14 | NM_001145809.2 | c.1918C>T | p.Arg640Trp | missense_variant | Exon 16 of 43 | ENST00000642316.2 | NP_001139281.1 | |
MYH14 | NM_001077186.2 | c.1918C>T | p.Arg640Trp | missense_variant | Exon 16 of 42 | NP_001070654.1 | ||
MYH14 | NM_024729.4 | c.1894C>T | p.Arg632Trp | missense_variant | Exon 15 of 41 | NP_079005.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152162Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000449 AC: 98AN: 218474 AF XY: 0.000568 show subpopulations
GnomAD4 exome AF: 0.000200 AC: 288AN: 1443290Hom.: 2 Cov.: 30 AF XY: 0.000242 AC XY: 173AN XY: 716216 show subpopulations
GnomAD4 genome AF: 0.000236 AC: 36AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74454 show subpopulations
ClinVar
Submissions by phenotype
not provided Benign:3
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Has not been previously published as pathogenic or benign to our knowledge -
not specified Uncertain:1
The p.Arg640Trp variant in MYH14 has been previously reported by our laboratory in 1 individual with hearing loss, and it has also been identified in 0.28% (75/ 26920) of South Asian chromosomes including 1 homozygote by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg640Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -
MYH14-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at