Genetic Variant MYL9:p.Thr97Met (chr20-36548137-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006097.5(MYL9):c.290C>T(p.Thr97Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MYL9
NM_006097.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Variant links:

Genes affected

MYL9 (HGNC:15754): (myosin light chain 9) Myosin, a structural component of muscle, consists of two heavy chains and four light chains. The protein encoded by this gene is a myosin light chain that may regulate muscle contraction by modulating the ATPase activity of myosin heads. The encoded protein binds calcium and is activated by myosin light chain kinase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MYL9 links:

DLGAP4-AS1 (HGNC:51223): (DLGAP4 antisense RNA 1)

DLGAP4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL9	NM_006097.5 link	c.290C>T	p.Thr97Met	missense_variant	Exon 3 of 4	ENST00000279022.7	NP_006088.2	P24844-1A0A384NY64
MYL9	NM_181526.3 link	c.185-940C>T		intron_variant	Intron 2 of 2		NP_852667.1	P24844-2
DLGAP4-AS1	NR_109939.1 link	n.467+23304G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL9	ENST00000279022.7 link	c.290C>T	p.Thr97Met	missense_variant	Exon 3 of 4	1	NM_006097.5	ENSP00000279022.2	P24844-1
MYL9	ENST00000346786.2 link	c.185-940C>T		intron_variant	Intron 2 of 2	1		ENSP00000217313.2	P24844-2
DLGAP4-AS1	ENST00000439595.5 link	n.467+23304G>A		intron_variant	Intron 2 of 4	1
DLGAP4-AS1	ENST00000425233.6 link	n.580-20213G>A		intron_variant	Intron 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250454

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.290C>T (p.T97M) alteration is located in exon 3 (coding exon 2) of the MYL9 gene. This alteration results from a C to T substitution at nucleotide position 290, causing the threonine (T) at amino acid position 97 to be replaced by a methionine (M). 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

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.94

Vest4

0.74

MutPred

0.40

Loss of phosphorylation at T97 (P = 0.0691);

MVP

0.83

MPC

0.55

ClinPred

0.87

GERP RS

4.9

Varity_R

0.51

gMVP

0.68

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

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