rs79760961

Variant names:

• chr17-18121038-G-T
• rs79760961
• NM_016239.4:c.2238G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-18121038-G-T
• chr17-18121038-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423237/MONDO:0019497/005

• 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:7
• Conservation: PhyloP100: 0.105
• 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)
• 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.2238G>T	p.Arg746Ser	missense	Exon 2 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.2238G>T	p.Arg746Ser	missense	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.1871G>T		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.00195 AC: 213 AN: 109144 AF XY: 0.00153

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 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

African (AFR) AF: 0.0450 AC: 1272 AN: 28242

American (AMR) AF: 0.00399 AC: 135 AN: 33832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24248

East Asian (EAS) AF: 0.00 AC: 0 AN: 32786

South Asian (SAS) AF: 0.0000913 AC: 7 AN: 76632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35260

Middle Eastern (MID) AF: 0.00537 AC: 26 AN: 4844

European-Non Finnish (NFE) AF: 0.000214 AC: 228 AN: 1066214

Other (OTH) AF: 0.00382 AC: 216 AN: 56554

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

African (AFR) AF: 0.0483 AC: 2003 AN: 41436

American (AMR) AF: 0.0106 AC: 161 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10154

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67630

Other (OTH) AF: 0.0125 AC: 26 AN: 2088

Alfa AF: 0.00944 Hom.: 4

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.081	T
Polyphen		0.29	B
Vest4		0.32
MutPred		0.36		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
Mutation Taster		=94/6	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: rs79760961; hg19: chr17-18024352;