Genetic Variant MYO15B:p.Asp2703Glu (chr17-75623807-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_001395058.1(MYO15B):c.8109T>G(p.Asp2703Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYO15B
NM_001395058.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.142

Variant links:

Genes affected

MYO15B (HGNC:14083): (myosin XVB) Predicted to enable ATP binding activity; actin binding activity; and cytoskeletal motor activity. Predicted to be located in brush border; cytoplasm; and cytoskeleton. Predicted to be part of myosin complex. [provided by Alliance of Genome Resources, Apr 2022]

MYO15B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15B	NM_001395058.1 link	c.8109T>G	p.Asp2703Glu	missense_variant	Exon 54 of 64	ENST00000645453.3	NP_001381987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15B	ENST00000645453.3 link	c.8109T>G	p.Asp2703Glu	missense_variant	Exon 54 of 64		NM_001395058.1	ENSP00000495242.3		A0A2R8YFM0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151982

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000195

AC:

107

AN:

549598

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

297578

show subpopulations

Gnomad4 AFR exome

AF:

0.000254

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000401

Gnomad4 EAS exome

AF:

0.000282

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000238

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000197

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000658

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital myopathy

Uncertain:1

Dec 20, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Asp2703Glu variant in MYO15B was identified by our study in 1 individual with dysphagia, ptosis, increased muscle fatigability, and muscle weakness. This variant was detected in cis with another variant of uncertain significance (p.c.2651+2T>A) in MYO15B. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for this phenotype. Given the limited information about this gene-disease relationship, the significance of the p.Asp2703Glu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in MYO15B we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

T;T

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.53

Sift4G

Pathogenic

0.0

D;.

Vest4

0.56

GERP RS

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over