rs200954595

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002470.4(MYH3):c.5457+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,614,084 control chromosomes in the GnomAD database, including 1,002 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 0.024 ( 65 hom., cov: 32)

Exomes 𝑓: 0.033 ( 937 hom. )

Consequence

MYH3
NM_002470.4 splice_region, intron

Scores

Splicing: ADA: 0.00002457

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.596

Publications

4 publications found

Variant links:

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

MYH3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 17-10630285-C-T is Benign according to our data. Variant chr17-10630285-C-T is described in ClinVar as Benign. ClinVar VariationId is 129665.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 = 0.0237 (3609/152200) while in subpopulation NFE AF = 0.0373 (2539/68002). AF 95% confidence interval is 0.0361. There are 65 homozygotes in GnomAd4. There are 1735 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 65 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.5457+3G>A		splice_region intron	N/A	NP_002461.2	P11055

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYH3	ENST00000583535.6	TSL:5 MANE Select	c.5457+3G>A	splice_region intron	N/A	ENSP00000464317.1	P11055
MYH3	ENST00000961194.1		c.5457+3G>A	splice_region intron	N/A	ENSP00000631253.1
MYHAS	ENST00000579914.2	TSL:4	n.705+16408C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3611

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00657

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0373

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0242

AC:

6089

AN:

251484

AF XY:

0.0245

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0361

Gnomad OTH exome

AF:

0.0283

GnomAD4 exome

AF:

0.0333

AC:

48633

AN:

1461884

Hom.:

937

Cov.:

AF XY:

0.0327

AC XY:

23808

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00514

AC:

172

AN:

33480

American (AMR)

AF:

0.0107

AC:

479

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0113

AC:

976

AN:

86258

European-Finnish (FIN)

AF:

0.0431

AC:

2303

AN:

53420

Middle Eastern (MID)

AF:

0.0219

AC:

126

AN:

5764

European-Non Finnish (NFE)

AF:

0.0384

AC:

42658

AN:

1112008

Other (OTH)

AF:

0.0281

AC:

1696

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3464

6929

10393

13858

17322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1582

3164

4746

6328

7910

<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:

0.0237

AC:

3609

AN:

152200

Hom.:

Cov.:

AF XY:

0.0233

AC XY:

1735

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00655

AC:

272

AN:

41552

American (AMR)

AF:

0.0159

AC:

243

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.0108

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0405

AC:

429

AN:

10582

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0373

AC:

2539

AN:

68002

Other (OTH)

AF:

0.0194

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

177

354

532

709

886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0302

Hom.:

Bravo

AF:

0.0206

Asia WGS

AF:

0.00578

AC:

AN:

3476

EpiCase

AF:

0.0329

EpiControl

AF:

0.0341

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Distal arthrogryposis type 2B1 (1)

Freeman-Sheldon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.4

(source)

DANN

Benign

0.79

PhyloP100

0.60

Mutation Taster

=18/82

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.088

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over