Genetic Variant NM_003802.3:c.5585A>G (chr17-10303278-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003802.3(MYH13):c.5585A>G(p.His1862Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,613,780 control chromosomes in the GnomAD database, including 9,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1862Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1164 hom., cov: 32)

Exomes 𝑓: 0.091 ( 8526 hom. )

Consequence

MYH13
NM_003802.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.94

Publications

23 publications found

Variant links:

Genes affected

MYH13 (HGNC:7571): (myosin heavy chain 13) Predicted to enable microfilament motor activity. Predicted to be involved in muscle contraction. Predicted to act upstream of or within cellular response to starvation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

MYH13 links:

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYHAS links:

LOC107985004 (HGNC:):

LOC107985004 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014390349).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH13	NM_003802.3 link	c.5585A>G	p.His1862Arg	missense_variant	Exon 39 of 41	ENST00000252172.9	NP_003793.2	Q9UKX3
LOC107985004	XR_001752791.3 link	n.95+11365T>C		intron_variant	Intron 1 of 4
LOC107985004	XR_007065617.1 link	n.95+11365T>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH13	ENST00000252172.9 link	c.5585A>G	p.His1862Arg	missense_variant	Exon 39 of 41	1	NM_003802.3	ENSP00000252172.4		Q9UKX3

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16546

AN:

151958

Hom.:

1155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.0330

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.0738

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.0712

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.0819

GnomAD2 exomes

AF:

0.125

AC:

31175

AN:

249804

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.0788

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.0728

Gnomad NFE exome

AF:

0.0722

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0912

AC:

133290

AN:

1461704

Hom.:

8526

Cov.:

AF XY:

0.0943

AC XY:

68583

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.146

AC:

4887

AN:

33476

American (AMR)

AF:

0.149

AC:

6678

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0788

AC:

2059

AN:

26116

East Asian (EAS)

AF:

0.319

AC:

12678

AN:

39694

South Asian (SAS)

AF:

0.207

AC:

17834

AN:

86232

European-Finnish (FIN)

AF:

0.0715

AC:

3817

AN:

53416

Middle Eastern (MID)

AF:

0.118

AC:

678

AN:

5766

European-Non Finnish (NFE)

AF:

0.0705

AC:

78423

AN:

1111896

Other (OTH)

AF:

0.103

AC:

6236

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

6245

12490

18734

24979

31224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3250

6500

9750

13000

16250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.109

AC:

16595

AN:

152076

Hom.:

1164

Cov.:

AF XY:

0.112

AC XY:

8331

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.144

AC:

5968

AN:

41490

American (AMR)

AF:

0.128

AC:

1954

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0738

AC:

256

AN:

3470

East Asian (EAS)

AF:

0.332

AC:

1702

AN:

5132

South Asian (SAS)

AF:

0.210

AC:

1008

AN:

4808

European-Finnish (FIN)

AF:

0.0712

AC:

754

AN:

10596

Middle Eastern (MID)

AF:

0.116

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0692

AC:

4704

AN:

67990

Other (OTH)

AF:

0.0877

AC:

185

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

699

1399

2098

2798

3497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0847

Hom.:

1783

Bravo

AF:

0.113

TwinsUK

AF:

0.0677

AC:

251

ALSPAC

AF:

0.0763

AC:

294

ESP6500AA

AF:

0.141

AC:

601

ESP6500EA

AF:

0.0685

AC:

584

ExAC

AF:

0.127

AC:

15349

Asia WGS

AF:

0.273

AC:

949

AN:

3478

EpiCase

AF:

0.0719

EpiControl

AF:

0.0732

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.1

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.092

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.47

.;T;.

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.4

N;N;N

PhyloP100

-1.9

PrimateAI

Benign

0.28

PROVEAN

Benign

2.6

.;.;N

REVEL

Benign

0.19

Sift

Benign

1.0

.;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.038

MPC

0.12

ClinPred

0.0037

GERP RS

0.54

Varity_R

0.046

gMVP

0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over