NM_138995.5:c.379C>T

Variant names:

• chr2-170214436-C-T
• rs199776057
• NM_138995.5:c.379C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_138995.5(MYO3B):​c.379C>T​(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: MYO3B NM_138995.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42
• Publications: 7 publications found

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]

ENSG00000308085 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3B	NM_138995.5	c.379C>T	p.Arg127Trp	missense_variant	Exon 4 of 35	ENST00000408978.9	NP_620482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3B	ENST00000408978.9	c.379C>T	p.Arg127Trp	missense_variant	Exon 4 of 35	1	NM_138995.5	ENSP00000386213.4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 249512 AF XY: 0.000192

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000230 AC: 336 AN: 1461818 Hom.: 0 Cov.: 33 AF XY: 0.000249 AC XY: 181 AN XY: 727216

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000287 AC: 319 AN: 1111962

Other (OTH) AF: 0.000166 AC: 10 AN: 60390

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000296 Hom.: 4

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379C>T (p.R127W) alteration is located in exon 4 (coding exon 4) of the MYO3B gene. This alteration results from a C to T substitution at nucleotide position 379, causing the arginine (R) at amino acid position 127 to be replaced by a tryptophan (W). 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	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.039	.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		2.4
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	D;D;.
Vest4		0.66
MVP		0.89
MPC		0.43
ClinPred		0.43	T
GERP RS		2.4
Varity_R		0.76
gMVP		0.52
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs199776057; hg19: chr2-171070946; COSMIC: COSV58697464;