Genetic Variant NM_138995.5:c.646C>A (chr2-170236033-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_138995.5(MYO3B):c.646C>A(p.Arg216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYO3B
NM_138995.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.05

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138995.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO3B	NM_138995.5	MANE Select	c.646C>A	p.Arg216Ser	missense	Exon 7 of 35	NP_620482.3	Q8WXR4-1
MYO3B	NM_001083615.4		c.646C>A	p.Arg216Ser	missense	Exon 7 of 34	NP_001077084.2	Q8WXR4-4
MYO3B	NR_045682.2		n.787C>A		non_coding_transcript_exon	Exon 7 of 36

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO3B	ENST00000408978.9	TSL:1 MANE Select	c.646C>A	p.Arg216Ser	missense	Exon 7 of 35	ENSP00000386213.4	Q8WXR4-1
MYO3B	ENST00000409044.7	TSL:1	c.646C>A	p.Arg216Ser	missense	Exon 7 of 34	ENSP00000386497.3	Q8WXR4-4
MYO3B	ENST00000442690.1	TSL:1	c.643C>A	p.Arg215Ser	missense	Exon 6 of 9	ENSP00000401160.1	H7C1M9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249358

AF XY:

0.00000739

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.79

PhyloP100

6.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.72

Gain of disorder (P = 0.062)

MVP

0.79

MPC

0.46

ClinPred

0.99

GERP RS

5.9

Varity_R

0.94

gMVP

0.84

Mutation Taster

=15/85

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over