Genetic Variant NM_001382347.1:c.3136G>A (chr15-52367055-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001382347.1(MYO5A):c.3136G>A(p.Val1046Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,794 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

MYO5A
NM_001382347.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.737

Publications

5 publications found

Variant links:

Genes affected

MYO5A (HGNC:7602): (myosin VA) This gene is one of three myosin V heavy-chain genes, belonging to the myosin gene superfamily. Myosin V is a class of actin-based motor proteins involved in cytoplasmic vesicle transport and anchorage, spindle-pole alignment and mRNA translocation. The protein encoded by this gene is abundant in melanocytes and nerve cells. Mutations in this gene cause Griscelli syndrome type-1 (GS1) and neuroectodermal melanolysosomal disease, or Elejalde disease. [provided by RefSeq, Sep 2023]

MYO5A Gene-Disease associations (from GenCC):

Griscelli syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Griscelli syndrome type 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008687317).

BP6

Variant 15-52367055-C-T is Benign according to our data. Variant chr15-52367055-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435922.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000972 (148/152326) while in subpopulation NFE AF = 0.00181 (123/68034). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382347.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO5A	NM_001382347.1	MANE Select	c.3136G>A	p.Val1046Met	missense	Exon 23 of 42	NP_001369276.1	Q9Y4I1-3
MYO5A	NM_001382348.1		c.3208G>A	p.Val1070Met	missense	Exon 24 of 43	NP_001369277.1
MYO5A	NM_001382349.1		c.3208G>A	p.Val1070Met	missense	Exon 24 of 42	NP_001369278.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO5A	ENST00000399233.7	TSL:5 MANE Select	c.3136G>A	p.Val1046Met	missense	Exon 23 of 42	ENSP00000382179.4	Q9Y4I1-3
MYO5A	ENST00000399231.8	TSL:1	c.3136G>A	p.Val1046Met	missense	Exon 23 of 41	ENSP00000382177.3	Q9Y4I1-1
MYO5A	ENST00000356338.11	TSL:1	c.3136G>A	p.Val1046Met	missense	Exon 23 of 41	ENSP00000348693.7	A0A8J8YWI7

Frequencies

GnomAD3 genomes

AF:

0.000972

AC:

148

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00103

AC:

256

AN:

249458

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.00161

AC:

2358

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1172

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33454

American (AMR)

AF:

0.000313

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00114

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00187

AC:

2084

AN:

1111720

Other (OTH)

AF:

0.00207

AC:

125

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152326

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41568

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000945

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000501

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Griscelli syndrome type 1 (1)

Inborn genetic diseases (1)

Intellectual disability (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.72

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.74

PrimateAI

Benign

0.44

PROVEAN

Benign

0.29

REVEL

Benign

0.025

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.016

Vest4

0.19

MVP

0.12

MPC

0.39

ClinPred

0.011

GERP RS

1.4

Varity_R

0.020

gMVP

0.13

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over