rs854772

Variant names:

• chr17-18151915-G-A
• rs854772
• NM_016239.4:c.7857G>A

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.7857G>A​(p.Gly2619Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,569,040 control chromosomes in the GnomAD database, including 273,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23974 hom., cov: 32)
  • Exomes 𝑓: 0.58 (249448 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.101
• Publications: 25 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

LOC124903944 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-18151915-G-A is Benign according to our data. Variant chr17-18151915-G-A is described in ClinVar as Benign. ClinVar VariationId is 45761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.621 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.7857G>A	p.Gly2619Gly	synonymous	Exon 41 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.7857G>A	p.Gly2619Gly	synonymous	Exon 41 of 66	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83400 AN: 151952 Hom.: 23939 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.0902

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.510 AC: 91292 AN: 179054 AF XY: 0.511

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.0916

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.584 AC: 827406 AN: 1416970 Hom.: 249448 Cov.: 57 AF XY: 0.579 AC XY: 405639 AN XY: 700210

African (AFR) AF: 0.512 AC: 16834 AN: 32886

American (AMR) AF: 0.410 AC: 15165 AN: 36964

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17135 AN: 25256

East Asian (EAS) AF: 0.101 AC: 3853 AN: 38122

South Asian (SAS) AF: 0.407 AC: 32722 AN: 80414

European-Finnish (FIN) AF: 0.582 AC: 29252 AN: 50298

Middle Eastern (MID) AF: 0.647 AC: 3693 AN: 5710

European-Non Finnish (NFE) AF: 0.621 AC: 675604 AN: 1088506

Other (OTH) AF: 0.564 AC: 33148 AN: 58814

GnomAD4 genome AF: 0.549 AC: 83493 AN: 152070 Hom.: 23974 Cov.: 32 AF XY: 0.537 AC XY: 39943 AN XY: 74346

African (AFR) AF: 0.508 AC: 21040 AN: 41456

American (AMR) AF: 0.477 AC: 7297 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2341 AN: 3466

East Asian (EAS) AF: 0.0908 AC: 470 AN: 5178

South Asian (SAS) AF: 0.391 AC: 1883 AN: 4818

European-Finnish (FIN) AF: 0.570 AC: 6035 AN: 10582

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42520 AN: 67950

Other (OTH) AF: 0.564 AC: 1192 AN: 2112

Alfa AF: 0.605 Hom.: 47408

Bravo AF: 0.541

Asia WGS AF: 0.278 AC: 967 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.77
CADD	Benign	0.88
DANN	Benign	0.57
PhyloP100		0.10
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: rs854772; hg19: chr17-18055229; COSMIC: COSV52753944; COSMIC: COSV52753944;