15-59205423-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0350

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]

ACMG classification

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=3, 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 GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1E	NM_004998.4	c.1593C>G	p.Ile531Met	missense_variant	15/28	ENST00000288235.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1E	ENST00000288235.9	c.1593C>G	p.Ile531Met	missense_variant	15/28	1	NM_004998.4	P1

Frequencies

GnomAD3 genomes AF: 0.00635 AC: 966 AN: 152098 Hom.: 3 Cov.: 32

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.: 11 AF XY: 0.00712 AC XY: 967 AN XY: 135902

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.: 69 Cov.: 32 AF XY: 0.00837 AC XY: 6086 AN XY: 727214

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.: 3 Cov.: 32 AF XY: 0.00671 AC XY: 499 AN XY: 74422

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.: 3

Bravo AF: 0.00465

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00251 AC: 11

ESP6500EA AF: 0.00851 AC: 73

ExAC AF: 0.00694 AC: 843

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00853

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYO1E: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.85
MVP		0.84
MPC		0.70
ClinPred		0.056	T
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

Other links and lift over

dbSNP: rs140447165; hg19: chr15-59497622;