17-18130805-A-T

Variant names:

• chr17-18130805-A-T
• rs201234482
• NM_016239.4:c.4033A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.4033A>T​(p.Ile1345Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,605,052 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: MYO15A NM_016239.4 missense, splice_region
• Scores: Splicing: ADA: 0.01628
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 2.39
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01732254).
• BP6: Variant 17-18130805-A-T is Benign according to our data. Variant chr17-18130805-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198880.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00181 (264/145546) while in subpopulation NFE AF = 0.00341 (228/66920). AF 95% confidence interval is 0.00304. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

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.4033A>T	p.Ile1345Leu	missense splice_region	Exon 8 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.4033A>T	p.Ile1345Leu	missense splice_region	Exon 8 of 66	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 264 AN: 145434 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000512

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00153 AC: 377 AN: 246486 AF XY: 0.00159

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000378

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.00326 AC: 4761 AN: 1459506 Hom.: 12 Cov.: 32 AF XY: 0.00313 AC XY: 2275 AN XY: 726164

African (AFR) AF: 0.000540 AC: 18 AN: 33328

American (AMR) AF: 0.000314 AC: 14 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.000604 AC: 32 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00413 AC: 4589 AN: 1110794

Other (OTH) AF: 0.00169 AC: 102 AN: 60254

GnomAD4 genome AF: 0.00181 AC: 264 AN: 145546 Hom.: 0 Cov.: 30 AF XY: 0.00171 AC XY: 121 AN XY: 70726

African (AFR) AF: 0.000653 AC: 25 AN: 38268

American (AMR) AF: 0.000412 AC: 6 AN: 14572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4854

South Asian (SAS) AF: 0.00 AC: 0 AN: 4536

European-Finnish (FIN) AF: 0.000512 AC: 5 AN: 9774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00341 AC: 228 AN: 66920

Other (OTH) AF: 0.00 AC: 0 AN: 2000

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00174

ESP6500AA AF: 0.000487 AC: 2

ESP6500EA AF: 0.00406 AC: 34

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)
-	-	1	MYO15A-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.28	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0090	D
Vest4		0.46
MutPred		0.41		Gain of helix (P = 0.0854)
MVP		0.84
ClinPred		0.023	T
GERP RS		2.7
Varity_R		0.19
gMVP		0.34
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201234482; hg19: chr17-18034119; COSMIC: COSV52755181;