Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001382347.1(MYO5A):c.3960A>T(p.Arg1320Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0398 in 1,612,686 control chromosomes in the GnomAD database, including 1,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 149 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1491 hom. )

Consequence

MYO5A
NM_001382347.1 missense, splice_region

Scores

Splicing: ADA: 0.7715

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.76

Publications

15 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019530058).

BP6

Variant 15-52343197-T-A is Benign according to our data. Variant chr15-52343197-T-A is described in ClinVar as Benign. ClinVar VariationId is 255652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0339 (5159/152296) while in subpopulation NFE AF = 0.0485 (3297/68014). AF 95% confidence interval is 0.0471. There are 149 homozygotes in GnomAd4. There are 2637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 149 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
MYO5A	NM_001382347.1	MANE Select	c.3960A>T	p.Arg1320Ser	missense splice_region	Exon 31 of 42	NP_001369276.1
MYO5A	NM_001382348.1		c.4032A>T	p.Arg1344Ser	missense splice_region	Exon 32 of 43	NP_001369277.1
MYO5A	NM_001382349.1		c.4032A>T	p.Arg1344Ser	missense splice_region	Exon 32 of 42	NP_001369278.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO5A	ENST00000399233.7	TSL:5 MANE Select	c.3960A>T	p.Arg1320Ser	missense splice_region	Exon 31 of 42	ENSP00000382179.4
MYO5A	ENST00000399231.8	TSL:1	c.3960A>T	p.Arg1320Ser	missense splice_region	Exon 31 of 41	ENSP00000382177.3
MYO5A	ENST00000399228.6	TSL:1	n.393A>T		splice_region non_coding_transcript_exon	Exon 5 of 16	ENSP00000382174.2

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5159

AN:

152178

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00661

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0485

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.0343

AC:

8563

AN:

249444

AF XY:

0.0345

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0453

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0404

AC:

59029

AN:

1460390

Hom.:

1491

Cov.:

AF XY:

0.0397

AC XY:

28812

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.00571

AC:

191

AN:

33452

American (AMR)

AF:

0.0116

AC:

517

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

479

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.0109

AC:

943

AN:

86234

European-Finnish (FIN)

AF:

0.100

AC:

5338

AN:

53360

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0446

AC:

49530

AN:

1110696

Other (OTH)

AF:

0.0330

AC:

1992

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2637

5273

7910

10546

13183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1704

3408

5112

6816

8520

<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:

0.0339

AC:

5159

AN:

152296

Hom.:

149

Cov.:

AF XY:

0.0354

AC XY:

2637

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00659

AC:

274

AN:

41582

American (AMR)

AF:

0.0152

AC:

232

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00871

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.103

AC:

1094

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0485

AC:

3297

AN:

68014

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

244

487

731

974

1218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0402

Hom.:

135

Bravo

AF:

0.0251

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.0407

AC:

339

ExAC

AF:

0.0336

AC:

4066

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0425

EpiControl

AF:

0.0365

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

M_CAP

Benign

0.017

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

3.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.090

REVEL

Benign

0.11

Sift

Benign

0.50

Sift4G

Benign

0.50

Polyphen

0.49

Vest4

0.59

MutPred

0.28

Gain of disorder (P = 0.0544)

MPC

0.42

ClinPred

0.023

GERP RS

5.9

Varity_R

0.14

gMVP

0.44

Mutation Taster

=59/41

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.77

dbscSNV1_RF

Benign

0.53

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs61731219

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over