chr15-52319154-C-T

Position:

chr15-52319154-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.010131419).

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: {Uncertain_significance=1, Benign=2}.

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 GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO5A	NM_001382347.1 linkuse as main transcript	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 linkuse as main transcript	c.5140G>A	p.Val1714Ile	missense_variant	39/42	5	NM_001382347.1		Q9Y4I1-3

Frequencies

GnomAD3 genomes

AF:

0.00259

AC:

394

AN:

152190

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00229

AC XY:

310

AN XY:

135408

show subpopulations

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.:

Cov.:

AF XY:

0.00406

AC XY:

2953

AN XY:

727246

show subpopulations

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.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00398

AC:

ExAC

AF:

0.00221

AC:

268

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00391

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

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

LIST_S2

Benign

0.85

T;T;T;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.010

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.40

N;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.57

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over