rs79760961

chr17-18121038-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016239.4(MYO15A):c.2238G>T(p.Arg746Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,509,772 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.015 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.105

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025066733).
• BP6: Variant 17-18121038-G-T is Benign according to our data. Variant chr17-18121038-G-T is described in ClinVar as [Benign]. Clinvar id is 226780.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (2207/151160) while in subpopulation AFR AF= 0.0483 (2003/41436). AF 95% confidence interval is 0.0466. There are 44 homozygotes in gnomad4. There are 1037 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.2238G>T	p.Arg746Ser	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.2238G>T	p.Arg746Ser	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.1871G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2201 AN: 151052 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00195 AC: 213 AN: 109144 Hom.: 6 AF XY: 0.00153 AC XY: 93 AN XY: 60676

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000503

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00139 AC: 1884 AN: 1358612 Hom.: 41 Cov.: 36 AF XY: 0.00125 AC XY: 839 AN XY: 670106

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000913

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.0146 AC: 2207 AN: 151160 Hom.: 44 Cov.: 32 AF XY: 0.0140 AC XY: 1037 AN XY: 73878

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.0125

Alfa AF: 0.00624 Hom.: 2

Bravo AF: 0.0169

ESP6500AA AF: 0.0259 AC: 51

ESP6500EA AF: 0.000403 AC: 2

ExAC AF: 0.00126 AC: 60

Asia WGS AF: 0.00272 AC: 9 AN: 3324

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg746Ser in Exon 02 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 2.6% (42/1612) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79760961). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -

Nonsyndromic genetic hearing loss Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 15, 2021

The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.8
Dann	Benign	0.85
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T;.;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.081	T;T;.
Polyphen		0.29	.;B;B
Vest4		0.32
MutPred		0.36		Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);
MVP		0.54
ClinPred		0.0097	T
GERP RS		1.1
Varity_R		0.097
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs79760961; hg19: chr17-18024352;