rs199621031

chr17-18163251-G-Achr17-18163251-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_016239.4(MYO15A):c.9620G>A(p.Arg3207His) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,138 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3207C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.47

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-18163251-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064985.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 17-18163251-G-A is Pathogenic according to our data. Variant chr17-18163251-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228973.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08375016).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.9620G>A	p.Arg3207His	missense_variant	59/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.9623G>A	p.Arg3208His	missense_variant	57/64
MYO15A	XM_017024714.3	c.9560G>A	p.Arg3187His	missense_variant	56/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.9620G>A	p.Arg3207His	missense_variant	59/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000441 AC: 11 AN: 249574 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00242

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: 0.000121 Hom.: 1

Bravo AF: 0.000672

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27375115, 27068579, 26226137) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3207 of the MYO15A protein (p.Arg3207His). This variant is present in population databases (rs199621031, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 26226137, 27068579; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228973). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 31, 2018	The p.Arg3207His variant (rs199621031) is reported in the medical literature in two individuals with nonsyndromic hearing loss, one who harbored a truncating variant on the other MYO15A allele and another who had a second missense variant in MYO15A (Bademci 2016 and Sommen 2016). This variant is reported in ClinVar (Variation ID: 228973) and is found in the general population with an allele frequency of 0.0036% (10/277,202 alleles) in the Genome Aggregation Database. The arginine at codon 3207 is highly conserved considering 11 species (Alamut v2.11) but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The MYO15A c.9620G>A (p.Arg3207His) variant has been reported in two studies and is found in two individuals with hearing loss in a compound heterozygous state with a frameshift variant and a missense variant, respectively (Bademci et al. 2016; Sommen et al. 2016). Control data are unavailable for the variant, which is reported at a frequency of 0.02404 in the Puerto Ricans in Puerto Rico population of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. The evidence for this variant is limited. The p.Arg3207His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2020

The p.Arg3207His variant in MYO15A has been reported in 7 individuals with hearing loss (two homozygous, four compound heterozygous with a second likely pathogenic variant, and one compound heterozygous with another variant of uncertain significance) (Bademci 2016, Sommen 2016, LMM data). This variant has been identified in 0.01% (5/35374) Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_Strong, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.090	T;D;D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.084	T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
Sift4G	Pathogenic	0.0010	D;D;.;D;.;D
Polyphen		0.94	.;P;P;.;.;.
Vest4		0.49
MVP		0.92
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs199621031; hg19: chr17-18066565;