rs143826293

Variant names:

• chr17-18155224-C-T
• rs143826293
• NM_016239.4:c.8339C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-18155224-C-T
• chr17-18155224-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016239.4(MYO15A):​c.8339C>T​(p.Thr2780Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00148 in 1,613,956 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2780T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: MYO15A NM_016239.4 missense, splice_region
• Scores: Splicing: ADA: 0.01123
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.40
• Publications: 2 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

LOC105371567 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_016239.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00789547).
• BP6: Variant 17-18155224-C-T is Benign according to our data. Variant chr17-18155224-C-T is described in ClinVar as Benign. ClinVar VariationId is 45768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00389 (593/152316) while in subpopulation AMR AF = 0.0364 (557/15302). AF 95% confidence interval is 0.0339. There are 20 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.8339C>T	p.Thr2780Met	missense splice_region	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.8339C>T	p.Thr2780Met	missense splice_region	Exon 46 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000418233.7	TSL:2	c.131C>T	p.Thr44Met	missense splice_region	Exon 4 of 24	ENSP00000408800.3	Q9UKN7-2
	MYO15A	ENST00000644795.1		c.131C>T	p.Thr44Met	missense splice_region	Exon 4 of 23	ENSP00000495720.1	A0A2R8Y712

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 594 AN: 152198 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00519 AC: 1292 AN: 249162 AF XY: 0.00403

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00123 AC: 1795 AN: 1461640 Hom.: 34 Cov.: 34 AF XY: 0.00108 AC XY: 784 AN XY: 727136

African (AFR) AF: 0.000508 AC: 17 AN: 33474

American (AMR) AF: 0.0358 AC: 1601 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111950

Other (OTH) AF: 0.00113 AC: 68 AN: 60384

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152316 Hom.: 20 Cov.: 33 AF XY: 0.00498 AC XY: 371 AN XY: 74482

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.0364 AC: 557 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00609

ExAC AF: 0.00336 AC: 407

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.92	L
PhyloP100		4.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Benign	0.38	T
Sift4G	Benign	0.12	T
Polyphen		0.46	P
Vest4		0.15
MVP		0.67
ClinPred		0.019	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.31
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.088
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: rs143826293; hg19: chr17-18058538;