3-108381559-C-T

Variant names:

• chr3-108381559-C-T
• rs201226192
• NM_014981.3:c.5767G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014981.3(MYH15):​c.5767G>A​(p.Val1923Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH15 NM_014981.3 missense, splice_region
• Scores: Splicing: ADA: 0.02581
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462

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]

LOC124900545 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03376949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH15	NM_014981.3	c.5767G>A	p.Val1923Ile	missense_variant, splice_region_variant	Exon 41 of 41	ENST00000693548.1	NP_055796.2
MYH15	XM_011512559.3	c.5827G>A	p.Val1943Ile	missense_variant, splice_region_variant	Exon 43 of 43		XP_011510861.1
LOC124900545	XR_007095998.1	n.20C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH15	ENST00000693548.1	c.5767G>A	p.Val1923Ile	missense_variant, splice_region_variant	Exon 41 of 41		NM_014981.3	ENSP00000508967.1
MYH15	ENST00000273353.5	c.5767G>A	p.Val1923Ile	missense_variant, splice_region_variant	Exon 42 of 42	1		ENSP00000273353.4
MYH15	ENST00000689784.1	c.4786G>A	p.Val1596Ile	missense_variant, splice_region_variant	Exon 33 of 33			ENSP00000509841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.15
Sift	Benign	0.52	T
Sift4G	Benign	0.44	T
Polyphen		0.0090	B
Vest4		0.12
MutPred		0.13		Loss of methylation at K1942 (P = 0.0517);
MVP		0.71
MPC		0.066
ClinPred		0.089	T
GERP RS		3.4
Varity_R		0.023
gMVP		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.026
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.070		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: rs201226192; hg19: chr3-108100406;