NM_004998.4:c.1593C>G

Variant names:

• chr15-59205423-G-C
• rs140447165
• NM_004998.4:c.1593C>G

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 0.0350
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 6

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 403214.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1E	NM_004998.4	MANE Select	c.1593C>G	p.Ile531Met	missense	Exon 15 of 28	NP_004989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1E	ENST00000288235.9	TSL:1 MANE Select	c.1593C>G	p.Ile531Met	missense	Exon 15 of 28	ENSP00000288235.4
	MYO1E	ENST00000884343.1		c.1593C>G	p.Ile531Met	missense	Exon 15 of 28	ENSP00000554402.1
	MYO1E	ENST00000884345.1		c.1566C>G	p.Ile522Met	missense	Exon 15 of 28	ENSP00000554404.1

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

GnomAD2 exomes AF: 0.00693 AC: 1742 AN: 251456 AF XY: 0.00712

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 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

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 55 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00184 AC: 159 AN: 86256

European-Finnish (FIN) AF: 0.0195 AC: 1040 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00991 AC: 11015 AN: 1111976

Other (OTH) AF: 0.00613 AC: 370 AN: 60396

GnomAD4 genome AF: 0.00635 AC: 967 AN: 152216 Hom.: 3 Cov.: 32 AF XY: 0.00671 AC XY: 499 AN XY: 74422

African (AFR) AF: 0.00140 AC: 58 AN: 41534

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4810

European-Finnish (FIN) AF: 0.0226 AC: 239 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00912 AC: 620 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Kidney disorder (1)
-	1	-	Microscopic hematuria (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.035
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
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs140447165; hg19: chr15-59497622; COSMIC: COSV106087107; COSMIC: COSV106087107;