Genetic Variant MYO5A:c.5409+4G>A (chr15-52317044-C-T) – ACMG Classification: Benign (-20 pts)

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.5409+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,613,148 control chromosomes in the GnomAD database, including 97 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 82 hom. )

Consequence

MYO5A
NM_001382347.1 splice_region, intron

Scores

Splicing: ADA: 0.0002138

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.367

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 15-52317044-C-T is Benign according to our data. Variant chr15-52317044-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211572.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 = 0.0065 (990/152284) while in subpopulation NFE AF = 0.0107 (727/68008). AF 95% confidence interval is 0.01. There are 15 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 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	Effect	Exon Rank	Protein	UniProt
MYO5A	NM_001382347.1	MANE Select	c.5409+4G>A	splice_region intron	N/A	NP_001369276.1	Q9Y4I1-3
MYO5A	NM_001382348.1		c.5481+4G>A	splice_region intron	N/A	NP_001369277.1
MYO5A	NM_001382349.1		c.5406+4G>A	splice_region intron	N/A	NP_001369278.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYO5A	ENST00000399233.7	TSL:5 MANE Select	c.5409+4G>A	splice_region intron	N/A	ENSP00000382179.4	Q9Y4I1-3
MYO5A	ENST00000399231.8	TSL:1	c.5334+4G>A	splice_region intron	N/A	ENSP00000382177.3	Q9Y4I1-1
MYO5A	ENST00000356338.11	TSL:1	c.5328+4G>A	splice_region intron	N/A	ENSP00000348693.7	A0A8J8YWI7

Frequencies

GnomAD3 genomes

AF:

0.00650

AC:

989

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00678

AC:

1690

AN:

249400

AF XY:

0.00699

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00343

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00727

GnomAD4 exome

AF:

0.00932

AC:

13611

AN:

1460864

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

6638

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33454

American (AMR)

AF:

0.00353

AC:

158

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.00649

AC:

560

AN:

86236

European-Finnish (FIN)

AF:

0.00360

AC:

192

AN:

53406

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0108

AC:

12047

AN:

1111124

Other (OTH)

AF:

0.00916

AC:

553

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

624

1248

1871

2495

3119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

440

880

1320

1760

2200

<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:

0.00650

AC:

990

AN:

152284

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41572

American (AMR)

AF:

0.00517

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00767

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

727

AN:

68008

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00883

Hom.:

Bravo

AF:

0.00674

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00981

EpiControl

AF:

0.0109

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Griscelli syndrome type 1 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.49

PhyloP100

0.37

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.022

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