NM_016239.4:c.8322C>T

Variant names:

• chr17-18155207-C-T
• rs712272
• NM_016239.4:c.8322C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.8322C>T​(p.Ser2774Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,613,392 control chromosomes in the GnomAD database, including 124,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9414 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115429 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.06
• Publications: 12 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

LOC105371567 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 17-18155207-C-T is Benign according to our data. Variant chr17-18155207-C-T is described in ClinVar as Benign. ClinVar VariationId is 45767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

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.8322C>T	p.Ser2774Ser	synonymous	Exon 46 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8322C>T	p.Ser2774Ser	synonymous	Exon 46 of 66	ENSP00000495481.1
	MYO15A	ENST00000418233.7	TSL:2	c.114C>T	p.Ser38Ser	synonymous	Exon 4 of 24	ENSP00000408800.3
	MYO15A	ENST00000644795.1		c.114C>T	p.Ser38Ser	synonymous	Exon 4 of 23	ENSP00000495720.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51246 AN: 152010 Hom.: 9414 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.0807

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.335 AC: 83264 AN: 248478 AF XY: 0.335

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.0872

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.389 AC: 567824 AN: 1461264 Hom.: 115429 Cov.: 52 AF XY: 0.383 AC XY: 278613 AN XY: 726936

African (AFR) AF: 0.233 AC: 7803 AN: 33472

American (AMR) AF: 0.282 AC: 12579 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10460 AN: 26132

East Asian (EAS) AF: 0.0981 AC: 3894 AN: 39686

South Asian (SAS) AF: 0.215 AC: 18507 AN: 86252

European-Finnish (FIN) AF: 0.437 AC: 23237 AN: 53132

Middle Eastern (MID) AF: 0.309 AC: 1782 AN: 5766

European-Non Finnish (NFE) AF: 0.421 AC: 467619 AN: 1111774

Other (OTH) AF: 0.363 AC: 21943 AN: 60380

GnomAD4 genome AF: 0.337 AC: 51264 AN: 152128 Hom.: 9414 Cov.: 33 AF XY: 0.331 AC XY: 24607 AN XY: 74362

African (AFR) AF: 0.238 AC: 9881 AN: 41502

American (AMR) AF: 0.299 AC: 4563 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1371 AN: 3468

East Asian (EAS) AF: 0.0812 AC: 420 AN: 5170

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4824

European-Finnish (FIN) AF: 0.422 AC: 4472 AN: 10602

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28350 AN: 67960

Other (OTH) AF: 0.326 AC: 687 AN: 2110

Alfa AF: 0.386 Hom.: 9768

Bravo AF: 0.322

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 3 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.6
DANN	Benign	0.87
PhyloP100		-1.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs712272; hg19: chr17-18058521; COSMIC: COSV52754131; COSMIC: COSV52754131;