chr17-18143875-G-A

Variant names:

• chr17-18143875-G-A
• rs2272571
• NM_016239.4:c.6052G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.6052G>A​(p.Gly2018Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,581,876 control chromosomes in the GnomAD database, including 20,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2502 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18406 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.25
• Publications: 37 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0833855E-5).
• BP6: Variant 17-18143875-G-A is Benign according to our data. Variant chr17-18143875-G-A is described in ClinVar as Benign. ClinVar VariationId is 45754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 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.6052G>A	p.Gly2018Arg	missense	Exon 28 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6052G>A	p.Gly2018Arg	missense	Exon 28 of 66	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24172 AN: 152100 Hom.: 2495 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.192 AC: 37975 AN: 198172 AF XY: 0.181

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 201600 AN: 1429658 Hom.: 18406 Cov.: 38 AF XY: 0.141 AC XY: 99713 AN XY: 708132

African (AFR) AF: 0.144 AC: 4739 AN: 32910

American (AMR) AF: 0.340 AC: 13465 AN: 39554

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2922 AN: 25576

East Asian (EAS) AF: 0.495 AC: 19060 AN: 38480

South Asian (SAS) AF: 0.158 AC: 13039 AN: 82358

European-Finnish (FIN) AF: 0.174 AC: 8819 AN: 50736

Middle Eastern (MID) AF: 0.0856 AC: 491 AN: 5738

European-Non Finnish (NFE) AF: 0.118 AC: 129667 AN: 1095072

Other (OTH) AF: 0.159 AC: 9398 AN: 59234

GnomAD4 genome AF: 0.159 AC: 24186 AN: 152218 Hom.: 2502 Cov.: 33 AF XY: 0.168 AC XY: 12482 AN XY: 74422

African (AFR) AF: 0.147 AC: 6125 AN: 41536

American (AMR) AF: 0.263 AC: 4023 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 387 AN: 3470

East Asian (EAS) AF: 0.507 AC: 2617 AN: 5164

South Asian (SAS) AF: 0.167 AC: 804 AN: 4826

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7884 AN: 67986

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.130 Hom.: 7021

Bravo AF: 0.167

TwinsUK AF: 0.117 AC: 434

ALSPAC AF: 0.113 AC: 434

ESP6500AA AF: 0.137 AC: 566

ESP6500EA AF: 0.115 AC: 967

ExAC AF: 0.157 AC: 18807

Asia WGS AF: 0.299 AC: 1039 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.73
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.000091	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.23		Gain of helix (P = 0.0425)
ClinPred		0.00029	T
GERP RS		2.7
Varity_R		0.029
gMVP		0.22
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2272571; hg19: chr17-18047189; COSMIC: COSV52753045; COSMIC: COSV52753045;