17-10494370-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005963.4(MYH1):c.5651G>A(p.Arg1884Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

MYH1
NM_005963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39

Publications

2 publications found

Variant links:

Genes affected

MYH1 (HGNC:7567): (myosin heavy chain 1) 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. Myosin heavy chains are encoded by a multigene family. In mammals at least 10 different myosin heavy chain (MYH) isoforms have been described from striated, smooth, and nonmuscle cells. These isoforms show expression that is spatially and temporally regulated during development. [provided by RefSeq, Jul 2008]

MYH1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20782799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH1	NM_005963.4 link	c.5651G>A	p.Arg1884Lys	missense_variant	Exon 39 of 40	ENST00000226207.6	NP_005954.3	P12882
MYH1	XM_017024675.2 link	c.5651G>A	p.Arg1884Lys	missense_variant	Exon 39 of 40		XP_016880164.1	P12882
MYHAS	NR_125367.1 link	n.168-73167C>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH1	ENST00000226207.6 link	c.5651G>A	p.Arg1884Lys	missense_variant	Exon 39 of 40	5	NM_005963.4	ENSP00000226207.5		P12882

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000306

AC:

AN:

251432

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000462

AC:

675

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

320

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000576

AC:

641

AN:

1111998

Other (OTH)

AF:

0.000282

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000217

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41448

American (AMR)

AF:

0.000458

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000471

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5651G>A (p.R1884K) alteration is located in exon 39 (coding exon 37) of the MYH1 gene. This alteration results from a G to A substitution at nucleotide position 5651, causing the arginine (R) at amino acid position 1884 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

M_CAP

Benign

0.041

MetaRNN

Benign

0.21

MetaSVM

Uncertain

-0.078

MutationAssessor

Uncertain

2.3

PhyloP100

3.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.50

Sift

Uncertain

0.011

Sift4G

Benign

0.13

Polyphen

0.13

Vest4

0.35

MVP

0.83

MPC

0.49

ClinPred

0.36

GERP RS

5.4

Varity_R

0.33

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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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17-10494370-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over