15-59205423-G-C

Position:

chr15-59205423-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004998.4(MYO1E):c.1593C>G(p.Ile531Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00848 in 1,614,048 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0064 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 69 hom. )

Consequence

MYO1E
NM_004998.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.0350

Variant links:

Genes affected

MYO1E (HGNC:7599): (myosin IE) This gene encodes a member of the nonmuscle class I myosins which are a subgroup of the unconventional myosin protein family. The unconventional myosin proteins function as actin-based molecular motors. Class I myosins are characterized by a head (motor) domain, a regulatory domain and a either a short or long tail domain. Among the class I myosins, this protein is distinguished by a long tail domain that is involved in crosslinking actin filaments. This protein localizes to the cytoplasm and may be involved in intracellular movement and membrane trafficking. Mutations in this gene are the cause of focal segmental glomerulosclerosis-6. This gene has been referred to as myosin IC in the literature but is distinct from the myosin IC gene located on chromosome 17. [provided by RefSeq, Jan 2012]

MYO1E links:

MYO1E (HGNC:):

MYO1E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015333265).

BP6

Variant 15-59205423-G-C is Benign according to our data. Variant chr15-59205423-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403214.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00635 (967/152216) while in subpopulation NFE AF= 0.00912 (620/68016). AF 95% confidence interval is 0.00852. There are 3 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1E	NM_004998.4 linkuse as main transcript	c.1593C>G	p.Ile531Met	missense_variant	15/28	ENST00000288235.9	NP_004989.2	Q12965Q4KMR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1E	ENST00000288235.9 linkuse as main transcript	c.1593C>G	p.Ile531Met	missense_variant	15/28	1	NM_004998.4	ENSP00000288235.4		Q12965

Frequencies

GnomAD3 genomes

AF:

0.00635

AC:

966

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00911

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00693

AC:

1742

AN:

251456

Hom.:

AF XY:

0.00712

AC XY:

967

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.00982

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00870

AC:

12722

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

6086

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00184

Gnomad4 FIN exome

AF:

0.0195

Gnomad4 NFE exome

AF:

0.00991

Gnomad4 OTH exome

AF:

0.00613

GnomAD4 genome

AF:

0.00635

AC:

967

AN:

152216

Hom.:

Cov.:

AF XY:

0.00671

AC XY:

499

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0226

Gnomad4 NFE

AF:

0.00912

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00740

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00251

AC:

ESP6500EA

AF:

0.00851

AC:

ExAC

AF:

0.00694

AC:

843

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00853

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MYO1E: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Microscopic hematuria

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Sep 15, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.85

MVP

0.84

MPC

0.70

ClinPred

0.056

GERP RS

-4.8

Varity_R

0.73

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over