rs16964944

Positions:

• chr15-52384195-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001382347.1(MYO5A):​c.1880T>C​(p.Met627Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,614,044 control chromosomes in the GnomAD database, including 1,457 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.053 (620 hom., cov: 32)
  • Exomes 𝑓: 0.011 (837 hom.)
• Consequence: MYO5A NM_001382347.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.890

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYO5A. . Gene score misZ 3.0961 (greater than the threshold 3.09). Trascript score misZ 5.1368 (greater than threshold 3.09). GenCC has associacion of gene with Griscelli syndrome type 3, Griscelli syndrome type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010196269).
• BP6: Variant 15-52384195-A-G is Benign according to our data. Variant chr15-52384195-A-G is described in ClinVar as [Benign]. Clinvar id is 255640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-52384195-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO5A	NM_001382347.1	c.1880T>C	p.Met627Thr	missense_variant	15/42	ENST00000399233.7	NP_001369276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO5A	ENST00000399233.7	c.1880T>C	p.Met627Thr	missense_variant	15/42	5	NM_001382347.1	ENSP00000382179.4

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8038 AN: 152072 Hom.: 617 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.0336

GnomAD3 exomes AF: 0.0232 AC: 5794 AN: 249480 Hom.: 334 AF XY: 0.0231 AC XY: 3128 AN XY: 135352

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.00802

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0113 AC: 16456 AN: 1461854 Hom.: 837 Cov.: 31 AF XY: 0.0122 AC XY: 8895 AN XY: 727232

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.00865

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.0601

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0529 AC: 8058 AN: 152190 Hom.: 620 Cov.: 32 AF XY: 0.0517 AC XY: 3851 AN XY: 74424

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.0581

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0133 Hom.: 265

Bravo AF: 0.0591

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.161 AC: 657

ESP6500EA AF: 0.00407 AC: 34

ExAC AF: 0.0276 AC: 3334

Asia WGS AF: 0.0610 AC: 215 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.5
DANN	Benign	0.29
DEOGEN2	Benign	0.19	T;.;T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.70	T;T;T;T;T;T
MetaRNN	Benign	0.0010	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.1	N;N;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.18	N;N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.82	T;T;.;T;T;T
Sift4G	Benign	0.87	T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.
Vest4		0.011
MPC		0.43
ClinPred		0.0041	T
GERP RS		-2.2
Varity_R		0.029
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs16964944; hg19: chr15-52676392;