rs1058219

chr15-52351367-G-A

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.3736C>T(p.Arg1246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,614,020 control chromosomes in the GnomAD database, including 21,616 homozygotes. In-silico tool predicts 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1246H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1810 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19806 hom.)
• Consequence: MYO5A NM_001382347.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.07

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 where missense usually causes diseases, MYO5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016999841).
• BP6: Variant 15-52351367-G-A is Benign according to our data. Variant chr15-52351367-G-A is described in ClinVar as [Benign]. Clinvar id is 255650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-52351367-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5A	NM_001382347.1	c.3736C>T	p.Arg1246Cys	missense_variant	28/42	ENST00000399233.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5A	ENST00000399233.7	c.3736C>T	p.Arg1246Cys	missense_variant	28/42	5	NM_001382347.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22847 AN: 152048 Hom.: 1816 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.156 AC: 38829 AN: 249556 Hom.: 3180 AF XY: 0.156 AC XY: 21155 AN XY: 135394

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.163 AC: 237836 AN: 1461854 Hom.: 19806 Cov.: 34 AF XY: 0.162 AC XY: 118133 AN XY: 727228

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.150 AC: 22838 AN: 152166 Hom.: 1810 Cov.: 32 AF XY: 0.148 AC XY: 10988 AN XY: 74408

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.176

Alfa AF: 0.168 Hom.: 3046

Bravo AF: 0.153

TwinsUK AF: 0.166 AC: 617

ALSPAC AF: 0.169 AC: 650

ESP6500AA AF: 0.102 AC: 414

ESP6500EA AF: 0.168 AC: 1402

ExAC AF: 0.154 AC: 18638

Asia WGS AF: 0.145 AC: 506 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.179

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Griscelli syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T;.;T;T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.;.;.;.;.;.
MutationTaster	Benign	0.00021	P;P;P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;.;D;D;D;D;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D;.;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D;D;T;T
Polyphen		0.59	P;D;.;.;.;.;.;.;.
Vest4		0.16
MPC		0.77
ClinPred		0.033	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.42

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: rs1058219; hg19: chr15-52643564; COSMIC: COSV62559286;