rs1058219

Variant names:

• chr15-52351367-G-A
• rs1058219
• NM_001382347.1:c.3736C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-52351367-G-A
• chr15-52351367-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1246P) 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:6
• Conservation: PhyloP100: 2.07
• Publications: 30 publications found

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Griscelli syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• 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 VariationId is 255650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5A	NM_001382347.1	MANE Select	c.3736C>T	p.Arg1246Cys	missense	Exon 28 of 42	NP_001369276.1	Q9Y4I1-3
	MYO5A	NM_001382348.1		c.3808C>T	p.Arg1270Cys	missense	Exon 29 of 43	NP_001369277.1
	MYO5A	NM_001382349.1		c.3808C>T	p.Arg1270Cys	missense	Exon 29 of 42	NP_001369278.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO5A	ENST00000399233.7	TSL:5 MANE Select	c.3736C>T	p.Arg1246Cys	missense	Exon 28 of 42	ENSP00000382179.4	Q9Y4I1-3
	MYO5A	ENST00000399231.8	TSL:1	c.3736C>T	p.Arg1246Cys	missense	Exon 28 of 41	ENSP00000382177.3	Q9Y4I1-1
	MYO5A	ENST00000356338.11	TSL:1	c.3736C>T	p.Arg1246Cys	missense	Exon 28 of 41	ENSP00000348693.7	A0A8J8YWI7

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

GnomAD2 exomes AF: 0.156 AC: 38829 AN: 249556 AF XY: 0.156

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 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

African (AFR) AF: 0.105 AC: 3507 AN: 33480

American (AMR) AF: 0.139 AC: 6233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5725 AN: 26136

East Asian (EAS) AF: 0.171 AC: 6790 AN: 39700

South Asian (SAS) AF: 0.152 AC: 13141 AN: 86258

European-Finnish (FIN) AF: 0.128 AC: 6863 AN: 53420

Middle Eastern (MID) AF: 0.206 AC: 1186 AN: 5764

European-Non Finnish (NFE) AF: 0.165 AC: 184005 AN: 1111978

Other (OTH) AF: 0.172 AC: 10386 AN: 60394

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

African (AFR) AF: 0.111 AC: 4592 AN: 41510

American (AMR) AF: 0.163 AC: 2499 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.192 AC: 994 AN: 5184

South Asian (SAS) AF: 0.154 AC: 742 AN: 4824

European-Finnish (FIN) AF: 0.123 AC: 1299 AN: 10592

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11384 AN: 67980

Other (OTH) AF: 0.176 AC: 372 AN: 2112

Alfa AF: 0.163 Hom.: 4757

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Griscelli syndrome type 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		0.59	P
Vest4		0.16
MPC		0.77
ClinPred		0.033	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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