rs61731219

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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:4

Conservation

PhyloP100: 3.76

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 -19 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=0.0019530058).

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 GnomAd4 at 149 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO5A	NM_001382347.1 linkuse as main transcript	c.3960A>T	p.Arg1320Ser	missense_variant, splice_region_variant	31/42	ENST00000399233.7	NP_001369276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO5A	ENST00000399233.7 linkuse as main transcript	c.3960A>T	p.Arg1320Ser	missense_variant, splice_region_variant	31/42	5	NM_001382347.1	ENSP00000382179		Q9Y4I1-3

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5159

AN:

152178

Hom.:

149

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0397

AC XY:

28812

AN XY:

726618

show subpopulations

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.:

AF XY:

0.0354

AC XY:

2637

AN XY:

74458

show subpopulations

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:

ESP6500EA

AF:

0.0407

AC:

339

ExAC

AF:

0.0336

AC:

4066

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0425

EpiControl

AF:

0.0365

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

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

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

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

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.53

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

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

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