15-52319154-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001382347.1(MYO5A):c.5140G>A(p.Val1714Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00406 in 1,614,196 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: MYO5A NM_001382347.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.17

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYO5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.010131419).
• BP6: Variant 15-52319154-C-T is Benign according to our data. Variant chr15-52319154-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235746.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152308) while in subpopulation NFE AF= 0.00415 (282/68016). AF 95% confidence interval is 0.00375. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5A	NM_001382347.1	c.5140G>A	p.Val1714Ile	missense_variant	39/42	ENST00000399233.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO5A	ENST00000399233.7	c.5140G>A	p.Val1714Ile	missense_variant	39/42	5	NM_001382347.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00239 AC: 596 AN: 249618 Hom.: 3 AF XY: 0.00229 AC XY: 310 AN XY: 135408

Gnomad AFR exome AF: 0.000709

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00421 AC: 6152 AN: 1461888 Hom.: 22 Cov.: 32 AF XY: 0.00406 AC XY: 2953 AN XY: 727246

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00486

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74468

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00359 Hom.: 1

Bravo AF: 0.00275

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00398 AC: 34

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO5A: PP2, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.;T;T;.;T;T
Eigen	Benign	0.0045
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T;T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.40	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.060	N;N;.;.;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.30	T;T;.;.;.;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T
Polyphen		0.0010	B;P;.;.;.;.;.
Vest4		0.25
MVP		0.48
MPC		0.73
ClinPred		0.020	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143298463; hg19: chr15-52611351; COSMIC: COSV99050900; COSMIC: COSV99050900;