3-108389002-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014981.3(MYH15):c.5503C>T(p.Leu1835Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,804 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (9 hom.)
• Consequence: MYH15 NM_014981.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.74

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003820002).
• BP6: Variant 3-108389002-G-A is Benign according to our data. Variant chr3-108389002-G-A is described in ClinVar as [Benign]. Clinvar id is 716847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00728 (1108/152268) while in subpopulation AFR AF= 0.025 (1037/41546). AF 95% confidence interval is 0.0237. There are 11 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH15	NM_014981.3	c.5503C>T	p.Leu1835Phe	missense_variant	38/41	ENST00000693548.1
MYH15	XM_011512559.3	c.5563C>T	p.Leu1855Phe	missense_variant	40/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH15	ENST00000693548.1	c.5503C>T	p.Leu1835Phe	missense_variant	38/41		NM_014981.3	P1
MYH15	ENST00000273353.5	c.5503C>T	p.Leu1835Phe	missense_variant	39/42	1		P1
MYH15	ENST00000689784.1	c.4522C>T	p.Leu1508Phe	missense_variant	30/33

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152150 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.00812

GnomAD3 exomes AF: 0.00182 AC: 454 AN: 248938 Hom.: 5 AF XY: 0.00138 AC XY: 186 AN XY: 135052

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000731 AC: 1069 AN: 1461536 Hom.: 9 Cov.: 30 AF XY: 0.000626 AC XY: 455 AN XY: 727072

Gnomad4 AFR exome AF: 0.0245

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00728 AC: 1108 AN: 152268 Hom.: 11 Cov.: 32 AF XY: 0.00719 AC XY: 535 AN XY: 74450

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00122 Hom.: 4

Bravo AF: 0.00804

ESP6500AA AF: 0.0226 AC: 91

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.00229 AC: 277

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.3
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.48	T
Polyphen		0.0050	B
Vest4		0.081
MVP		0.52
MPC		0.22
ClinPred		0.0051	T
GERP RS		-1.2
Varity_R		0.039
gMVP		0.056

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

Publications

LitVar

Other links and lift over

dbSNP: rs61745216; hg19: chr3-108107849;