2-170369295-C-A

Variant names:

• chr2-170369295-C-A
• rs754766991
• NM_138995.5:c.889C>A

Variant summary

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

The NM_138995.5(MYO3B):​c.889C>A​(p.His297Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYO3B NM_138995.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

Genes affected

MYO3B (HGNC:15576): (myosin IIIB) This gene encodes one of the class III myosins. Myosins are ATPases, activated by actin, that move along actin filaments in the cell. This class of myosins are characterized by an amino-terminal kinase domain and shown to be present in photoreceptors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

MYO3B-AS1 (HGNC:40713): (MYO3B antisense RNA 1)

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=0.20289183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3B	NM_138995.5	c.889C>A	p.His297Asn	missense_variant	Exon 9 of 35	ENST00000408978.9	NP_620482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3B	ENST00000408978.9	c.889C>A	p.His297Asn	missense_variant	Exon 9 of 35	1	NM_138995.5	ENSP00000386213.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249196 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461520 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727070

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.889C>A (p.H297N) alteration is located in exon 9 (coding exon 9) of the MYO3B gene. This alteration results from a C to A substitution at nucleotide position 889, causing the histidine (H) at amino acid position 297 to be replaced by an asparagine (N). 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	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.018	.;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.36	.;.;T
Polyphen		0.14	B;B;.
Vest4		0.51
MutPred		0.46		Gain of catalytic residue at H297 (P = 0.0296);Gain of catalytic residue at H297 (P = 0.0296);.;
MVP		0.46
MPC		0.082
ClinPred		0.24	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.45

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: rs754766991; hg19: chr2-171225805;