rs2955366

Variant names:

• chr17-18120699-A-G
• rs2955366
• NM_016239.4:c.1899A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.1899A>G​(p.Pro633Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,543,570 control chromosomes in the GnomAD database, including 113,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14513 hom., cov: 31)
  • Exomes 𝑓: 0.36 (98680 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.111
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant 17-18120699-A-G is Benign according to our data. Variant chr17-18120699-A-G is described in ClinVar as Benign. ClinVar VariationId is 226778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 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.1899A>G	p.Pro633Pro	synonymous	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.1899A>G	p.Pro633Pro	synonymous	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.1532A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 63952 AN: 150662 Hom.: 14479 Cov.: 31

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.405

GnomAD2 exomes AF: 0.459 AC: 68279 AN: 148870 AF XY: 0.468

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.358 AC: 499011 AN: 1392804 Hom.: 98680 Cov.: 43 AF XY: 0.369 AC XY: 254271 AN XY: 689474

African (AFR) AF: 0.536 AC: 16181 AN: 30180

American (AMR) AF: 0.493 AC: 17834 AN: 36202

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 10418 AN: 24766

East Asian (EAS) AF: 0.655 AC: 23495 AN: 35878

South Asian (SAS) AF: 0.701 AC: 56095 AN: 80034

European-Finnish (FIN) AF: 0.383 AC: 14313 AN: 37374

Middle Eastern (MID) AF: 0.453 AC: 2153 AN: 4758

European-Non Finnish (NFE) AF: 0.309 AC: 335575 AN: 1085802

Other (OTH) AF: 0.397 AC: 22947 AN: 57810

GnomAD4 genome AF: 0.425 AC: 64035 AN: 150766 Hom.: 14513 Cov.: 31 AF XY: 0.435 AC XY: 32017 AN XY: 73634

African (AFR) AF: 0.524 AC: 21518 AN: 41056

American (AMR) AF: 0.469 AC: 7121 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1441 AN: 3462

East Asian (EAS) AF: 0.637 AC: 3225 AN: 5066

South Asian (SAS) AF: 0.705 AC: 3390 AN: 4806

European-Finnish (FIN) AF: 0.415 AC: 4284 AN: 10330

Middle Eastern (MID) AF: 0.390 AC: 113 AN: 290

European-Non Finnish (NFE) AF: 0.321 AC: 21719 AN: 67580

Other (OTH) AF: 0.405 AC: 846 AN: 2090

Alfa AF: 0.361 Hom.: 3464

Bravo AF: 0.427

Asia WGS AF: 0.647 AC: 2223 AN: 3438

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Autosomal recessive nonsyndromic hearing loss 3 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.1
DANN	Benign	0.26
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs2955366; hg19: chr17-18024013; COSMIC: COSV52751200;