rs3900940

chr3-108428881-T-Achr3-108428881-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014981.3(MYH15):c.3313A>T(p.Thr1105Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,724 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: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYH15 NM_014981.3 missense, splice_region
• Scores: Splicing: ADA: 0.0008983
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09736058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH15	NM_014981.3	c.3313A>T	p.Thr1105Ser	missense_variant, splice_region_variant	27/41	ENST00000693548.1
MYH15	XM_011512559.3	c.3373A>T	p.Thr1125Ser	missense_variant, splice_region_variant	29/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH15	ENST00000693548.1	c.3313A>T	p.Thr1105Ser	missense_variant, splice_region_variant	27/41		NM_014981.3	P1
MYH15	ENST00000273353.5	c.3313A>T	p.Thr1105Ser	missense_variant, splice_region_variant	28/42	1		P1
MYH15	ENST00000689784.1	c.2332A>T	p.Thr778Ser	missense_variant, splice_region_variant	19/33
MYH15	ENST00000478998.5	n.1365A>T		splice_region_variant, non_coding_transcript_exon_variant	10/16	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233408 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000332

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442724 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 716850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000254

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.5
Dann	Benign	0.95
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.14
Sift	Uncertain	0.015	D
Sift4G	Benign	0.23	T
Polyphen		0.28	B
Vest4		0.048
MutPred		0.25		Loss of ubiquitination at K1128 (P = 0.0787);
MVP		0.62
MPC		0.075
ClinPred		0.12	T
GERP RS		-1.7
Varity_R		0.038
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.098
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;