rs61363656

chr15-52416305-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382347.1(MYO5A):c.456-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0525 in 1,613,504 control chromosomes in the GnomAD database, including 2,705 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 0.051 (272 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2433 hom.)
• Consequence: MYO5A NM_001382347.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002633
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.652

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-52416305-T-C is Benign according to our data. Variant chr15-52416305-T-C is described in ClinVar as [Benign]. Clinvar id is 255654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5A	NM_001382347.1	c.456-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399233.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5A	ENST00000399233.7	c.456-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001382347.1

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7741 AN: 152090 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0570

GnomAD3 exomes AF: 0.0614 AC: 15233 AN: 248056 Hom.: 627 AF XY: 0.0601 AC XY: 8090 AN XY: 134546

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.0577

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.0721

Gnomad FIN exome AF: 0.0645

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0526 AC: 76911 AN: 1461296 Hom.: 2433 Cov.: 31 AF XY: 0.0530 AC XY: 38506 AN XY: 726940

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.0566

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.0749

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.0469

Gnomad4 OTH exome AF: 0.0588

GnomAD4 genome AF: 0.0508 AC: 7735 AN: 152208 Hom.: 272 Cov.: 32 AF XY: 0.0534 AC XY: 3974 AN XY: 74418

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.0608

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.0728

Gnomad4 FIN AF: 0.0660

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0569

Alfa AF: 0.0474 Hom.: 81

Bravo AF: 0.0490

Asia WGS AF: 0.104 AC: 361 AN: 3478

EpiCase AF: 0.0463

EpiControl AF: 0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Griscelli syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.6
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.14
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

LitVar

Other links and lift over

dbSNP: rs61363656; hg19: chr15-52708502; COSMIC: COSV62560772;