3-108428881-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014981.3(MYH15):c.3313A>G(p.Thr1105Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,593,946 control chromosomes in the GnomAD database, including 63,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4824 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58483 hom.)
• Consequence: MYH15 NM_014981.3 missense, splice_region
• Scores: Splicing: ADA: 0.00004654
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

Genes affected

MYH15 (HGNC:31073): (myosin heavy chain 15) Predicted to enable several functions, including ATP binding activity; actin filament binding activity; and calmodulin binding activity. Predicted to be involved in extraocular skeletal muscle development. Located in cytosol and intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002068162).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH15	NM_014981.3	c.3313A>G	p.Thr1105Ala	missense_variant, splice_region_variant	27/41	ENST00000693548.1
MYH15	XM_011512559.3	c.3373A>G	p.Thr1125Ala	missense_variant, splice_region_variant	29/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH15	ENST00000693548.1	c.3313A>G	p.Thr1105Ala	missense_variant, splice_region_variant	27/41		NM_014981.3	P1
MYH15	ENST00000273353.5	c.3313A>G	p.Thr1105Ala	missense_variant, splice_region_variant	28/42	1		P1
MYH15	ENST00000689784.1	c.2332A>G	p.Thr778Ala	missense_variant, splice_region_variant	19/33
MYH15	ENST00000478998.5	n.1365A>G		splice_region_variant, non_coding_transcript_exon_variant	10/16	2

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35857 AN: 151836 Hom.: 4822 Cov.: 31

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.00810

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.240 AC: 55910 AN: 233408 Hom.: 7658 AF XY: 0.244 AC XY: 30948 AN XY: 126716

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.00696

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.278 AC: 400714 AN: 1441992 Hom.: 58483 Cov.: 35 AF XY: 0.276 AC XY: 198069 AN XY: 716526

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.00392

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.236 AC: 35869 AN: 151954 Hom.: 4824 Cov.: 31 AF XY: 0.232 AC XY: 17252 AN XY: 74270

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.00792

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.243

Alfa AF: 0.284 Hom.: 15356

Bravo AF: 0.224

TwinsUK AF: 0.299 AC: 1107

ALSPAC AF: 0.296 AC: 1142

ESP6500AA AF: 0.142 AC: 524

ESP6500EA AF: 0.288 AC: 2352

ExAC AF: 0.238 AC: 28769

Asia WGS AF: 0.136 AC: 474 AN: 3478

EpiCase AF: 0.308

EpiControl AF: 0.307

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.7
Dann	Benign	0.12
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.82	N
MutationTaster	Benign	0.34	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.027
MPC		0.079
ClinPred		0.0032	T
GERP RS		-1.7
Varity_R		0.024
gMVP		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs3900940; hg19: chr3-108147728; COSMIC: COSV56307247;