3-108391778-G-C

Variant names:

• chr3-108391778-G-C
• NM_014981.3:c.5412C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014981.3(MYH15):​c.5412C>G​(p.Ile1804Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH15 NM_014981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH15	NM_014981.3	c.5412C>G	p.Ile1804Met	missense_variant	Exon 37 of 41	ENST00000693548.1	NP_055796.2
MYH15	XM_011512559.3	c.5472C>G	p.Ile1824Met	missense_variant	Exon 39 of 43		XP_011510861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH15	ENST00000693548.1	c.5412C>G	p.Ile1804Met	missense_variant	Exon 37 of 41		NM_014981.3	ENSP00000508967.1
MYH15	ENST00000273353.5	c.5412C>G	p.Ile1804Met	missense_variant	Exon 38 of 42	1		ENSP00000273353.4
MYH15	ENST00000689784.1	c.4431C>G	p.Ile1477Met	missense_variant	Exon 29 of 33			ENSP00000509841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5472C>G (p.I1824M) alteration is located in exon 38 (coding exon 38) of the MYH15 gene. This alteration results from a C to G substitution at nucleotide position 5472, causing the isoleucine (I) at amino acid position 1824 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.041	D
Polyphen		0.92	P
Vest4		0.37
MutPred		0.57		Gain of ubiquitination at K1826 (P = 0.1047);
MVP		0.87
MPC		0.44
ClinPred		0.72	D
GERP RS		2.1
Varity_R		0.21
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-108110625;