rs377389290

Variant names:

• chr17-18157749-G-A
• rs377389290
• NM_016239.4:c.8816G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016239.4(MYO15A):​c.8816G>A​(p.Arg2939His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000921 in 1,606,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2939R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.55
• Publications: 2 publications found

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]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03335142).
• BP6: Variant 17-18157749-G-A is Benign according to our data. Variant chr17-18157749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 322173.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.8816G>A	p.Arg2939His	missense	Exon 51 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8816G>A	p.Arg2939His	missense	Exon 51 of 66	ENSP00000495481.1
	MYO15A	ENST00000418233.7	TSL:2	c.608G>A	p.Arg203His	missense	Exon 9 of 24	ENSP00000408800.3
	MYO15A	ENST00000644795.1		c.608G>A	p.Arg203His	missense	Exon 9 of 23	ENSP00000495720.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 40 AN: 239232 AF XY: 0.000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000548

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000922 AC: 134 AN: 1454022 Hom.: 0 Cov.: 33 AF XY: 0.0000967 AC XY: 70 AN XY: 723734

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111844

Other (OTH) AF: 0.000232 AC: 14 AN: 60324

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.045
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.036	D
Polyphen		0.14	B
Vest4		0.30
MVP		0.31
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.077
gMVP		0.61
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs377389290; hg19: chr17-18061063; COSMIC: COSV52765187; COSMIC: COSV52765187;