dbSNP rs117029104: MYO5A:c.2817+3G>A (chr15-52372121-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.2817+3G>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 0.0266 in 1,613,506 control chromosomes in the GnomAD database, including 700 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 0.019 ( 37 hom., cov: 32)

Exomes 𝑓: 0.027 ( 663 hom. )

Consequence

MYO5A
NM_001382347.1 splice_region, intron

Scores

Splicing: ADA: 0.0004716

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.00300

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 15-52372121-C-T is Benign according to our data. Variant chr15-52372121-C-T is described in ClinVar as Benign. ClinVar VariationId is 255644.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 = 0.0193 (2934/152286) while in subpopulation NFE AF = 0.0288 (1962/68034). AF 95% confidence interval is 0.0278. There are 37 homozygotes in GnomAd4. There are 1418 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 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.2817+3G>A	splice_region intron	N/A	NP_001369276.1	Q9Y4I1-3
MYO5A	NM_001382348.1		c.2889+3G>A	splice_region intron	N/A	NP_001369277.1
MYO5A	NM_001382349.1		c.2889+3G>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.2817+3G>A	splice_region intron	N/A	ENSP00000382179.4	Q9Y4I1-3
MYO5A	ENST00000399231.8	TSL:1	c.2817+3G>A	splice_region intron	N/A	ENSP00000382177.3	Q9Y4I1-1
MYO5A	ENST00000356338.11	TSL:1	c.2817+3G>A	splice_region intron	N/A	ENSP00000348693.7	A0A8J8YWI7

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2933

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0406

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0288

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0186

AC:

4638

AN:

248934

AF XY:

0.0183

show subpopulations

Gnomad AFR exome

AF:

0.00478

Gnomad AMR exome

AF:

0.00794

Gnomad ASJ exome

AF:

0.00607

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.0386

Gnomad NFE exome

AF:

0.0276

Gnomad OTH exome

AF:

0.0190

GnomAD4 exome

AF:

0.0273

AC:

39942

AN:

1461220

Hom.:

663

Cov.:

AF XY:

0.0265

AC XY:

19295

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.00475

AC:

159

AN:

33458

American (AMR)

AF:

0.00843

AC:

377

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00562

AC:

147

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00565

AC:

487

AN:

86230

European-Finnish (FIN)

AF:

0.0394

AC:

2107

AN:

53418

Middle Eastern (MID)

AF:

0.00570

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.0317

AC:

35223

AN:

1111966

Other (OTH)

AF:

0.0233

AC:

1408

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2033

4066

6098

8131

10164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1328

2656

3984

5312

6640

<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:

0.0193

AC:

2934

AN:

152286

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1418

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00577

AC:

240

AN:

41562

American (AMR)

AF:

0.0126

AC:

193

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.00476

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0406

AC:

430

AN:

10580

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0288

AC:

1962

AN:

68034

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

140

279

419

558

698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0229

Hom.:

Bravo

AF:

0.0170

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0257

EpiControl

AF:

0.0238

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.7

(source)

DANN

Benign

0.63

PhyloP100

0.0030

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00047

dbscSNV1_RF

Benign

0.050

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