rs61731219

chr15-52343197-T-Achr15-52343197-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001382347.1(MYO5A):c.3960A>T(p.Arg1320Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0398 in 1,612,686 control chromosomes in the GnomAD database, including 1,640 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 0.034 (149 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1491 hom.)
• Consequence: MYO5A NM_001382347.1 missense, splice_region
• Scores: Splicing: ADA: 0.7715
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.76

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=0.0019530058).
• BP6: Variant 15-52343197-T-A is Benign according to our data. Variant chr15-52343197-T-A is described in ClinVar as [Benign]. Clinvar id is 255652.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 = 0.0339 (5159/152296) while in subpopulation NFE AF= 0.0485 (3297/68014). AF 95% confidence interval is 0.0471. There are 149 homozygotes in gnomad4. There are 2637 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 149 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5A	NM_001382347.1	c.3960A>T	p.Arg1320Ser	missense_variant, splice_region_variant	31/42	ENST00000399233.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5A	ENST00000399233.7	c.3960A>T	p.Arg1320Ser	missense_variant, splice_region_variant	31/42	5	NM_001382347.1

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5159 AN: 152178 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0343 AC: 8563 AN: 249444 Hom.: 237 AF XY: 0.0345 AC XY: 4675 AN XY: 135332

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0404 AC: 59029 AN: 1460390 Hom.: 1491 Cov.: 31 AF XY: 0.0397 AC XY: 28812 AN XY: 726618

Gnomad4 AFR exome AF: 0.00571

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0446

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0339 AC: 5159 AN: 152296 Hom.: 149 Cov.: 32 AF XY: 0.0354 AC XY: 2637 AN XY: 74458

Gnomad4 AFR AF: 0.00659

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0402 Hom.: 135

Bravo AF: 0.0251

TwinsUK AF: 0.0388 AC: 144

ALSPAC AF: 0.0400 AC: 154

ESP6500AA AF: 0.00614 AC: 24

ESP6500EA AF: 0.0407 AC: 339

ExAC AF: 0.0336 AC: 4066

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0425

EpiControl AF: 0.0365

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.064	T;T;.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.090	N;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.50	T;.;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T
Polyphen		0.49	P;.;.;D;D
Vest4		0.59
MutPred		0.28		Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);.;.;
MPC		0.42
ClinPred		0.023	T
GERP RS		5.9
Varity_R		0.14
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.090		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: rs61731219; hg19: chr15-52635394; COSMIC: COSV62560618;