15-59138224-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_004998.4(MYO1E):c.3224A>G(p.Asn1075Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000873 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: MYO1E NM_004998.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11880663).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/152340) while in subpopulation EAS AF= 0.000578 (3/5188). AF 95% confidence interval is 0.000157. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1E	NM_004998.4	c.3224A>G	p.Asn1075Ser	missense_variant	27/28	ENST00000288235.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1E	ENST00000288235.9	c.3224A>G	p.Asn1075Ser	missense_variant	27/28	1	NM_004998.4	P1
MYO1E	ENST00000559412.1	c.129+68A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251460 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135902

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74490

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1075 of the MYO1E protein (p.Asn1075Ser). This variant is present in population databases (rs188694704, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MYO1E-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.080
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.031	D
Sift4G	Uncertain	0.016	D
Polyphen		0.12	B
Vest4		0.22
MVP		0.67
MPC		0.14
ClinPred		0.053	T
GERP RS		4.7
Varity_R		0.10
gMVP		0.067

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: rs188694704; hg19: chr15-59430423;