rs854777

Variant names:

• chr17-18143584-T-C
• rs854777
• NM_016239.4:c.5929T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-18143584-T-C
• chr17-18143584-T-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 15730/17934) of the p.Cys1977Arg variant in the MYO15A gene is 86.6% for African chromosomes (including 6913 homozygous observations) by gnomAD v2.1, 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). ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136998/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.78 (46916 hom., cov: 31)
  • Exomes 𝑓: 0.74 (391627 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: -0.0330
• Publications: 36 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)
• 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: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.5929T>C	p.Cys1977Arg	missense	Exon 26 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.5929T>C	p.Cys1977Arg	missense	Exon 26 of 66	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118665 AN: 151916 Hom.: 46845 Cov.: 31

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.778

GnomAD2 exomes AF: 0.732 AC: 123555 AN: 168796 AF XY: 0.721

Gnomad AFR exome AF: 0.877

Gnomad AMR exome AF: 0.778

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.749

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.743 AC: 1047626 AN: 1409088 Hom.: 391627 Cov.: 78 AF XY: 0.738 AC XY: 513806 AN XY: 696050

African (AFR) AF: 0.884 AC: 28523 AN: 32250

American (AMR) AF: 0.778 AC: 28771 AN: 36972

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 20615 AN: 25286

East Asian (EAS) AF: 0.620 AC: 22802 AN: 36796

South Asian (SAS) AF: 0.588 AC: 47038 AN: 80060

European-Finnish (FIN) AF: 0.761 AC: 38016 AN: 49932

Middle Eastern (MID) AF: 0.766 AC: 3896 AN: 5088

European-Non Finnish (NFE) AF: 0.751 AC: 814125 AN: 1084362

Other (OTH) AF: 0.751 AC: 43840 AN: 58342

GnomAD4 genome AF: 0.781 AC: 118797 AN: 152034 Hom.: 46916 Cov.: 31 AF XY: 0.777 AC XY: 57713 AN XY: 74324

African (AFR) AF: 0.878 AC: 36411 AN: 41482

American (AMR) AF: 0.778 AC: 11863 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 2802 AN: 3472

East Asian (EAS) AF: 0.627 AC: 3230 AN: 5150

South Asian (SAS) AF: 0.578 AC: 2775 AN: 4804

European-Finnish (FIN) AF: 0.755 AC: 7995 AN: 10584

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51249 AN: 67972

Other (OTH) AF: 0.780 AC: 1645 AN: 2110

Alfa AF: 0.762 Hom.: 65548

Bravo AF: 0.788

TwinsUK AF: 0.748 AC: 2773

ALSPAC AF: 0.746 AC: 2875

ESP6500AA AF: 0.871 AC: 3531

ESP6500EA AF: 0.770 AC: 6375

ExAC AF: 0.684 AC: 73724

Asia WGS AF: 0.608 AC: 2116 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autosomal recessive nonsyndromic hearing loss 3 (3)
-	-	3	not provided (3)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.6
DANN	Benign	0.45
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.033
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.029
ClinPred		0.0012	T
GERP RS		1.2
Varity_R		0.066
gMVP		0.46
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs854777; hg19: chr17-18046898; COSMIC: COSV52752023; COSMIC: COSV52752023;