chr18-3168934-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003803.4(MYOM1):​c.1222G>A​(p.Asp408Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D408G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.56

Publications

1 publications found
Variant links:
Genes affected
MYOM1 (HGNC:7613): (myomesin 1) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
MYOM1 Gene-Disease associations (from GenCC):
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.087007016).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYOM1NM_003803.4 linkc.1222G>A p.Asp408Asn missense_variant Exon 9 of 38 ENST00000356443.9 NP_003794.3 P52179-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYOM1ENST00000356443.9 linkc.1222G>A p.Asp408Asn missense_variant Exon 9 of 38 1 NM_003803.4 ENSP00000348821.4 P52179-1
MYOM1ENST00000261606.11 linkc.1222G>A p.Asp408Asn missense_variant Exon 9 of 37 1 ENSP00000261606.7 P52179-2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000403
AC:
10
AN:
248128
AF XY:
0.0000520
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.000498
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461464
Hom.:
0
Cov.:
33
AF XY:
0.0000193
AC XY:
14
AN XY:
726986
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.000134
AC:
6
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53380
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000108
AC:
12
AN:
1111760
Other (OTH)
AF:
0.000116
AC:
7
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000525
AC:
8
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74446
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41566
American (AMR)
AF:
0.000327
AC:
5
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000843
Hom.:
0
Bravo
AF:
0.0000869
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 21, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1222G>A (p.D408N) alteration is located in exon 9 (coding exon 8) of the MYOM1 gene. This alteration results from a G to A substitution at nucleotide position 1222, causing the aspartic acid (D) at amino acid position 408 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy Uncertain:1
Nov 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 408 of the MYOM1 protein (p.Asp408Asn). This variant is present in population databases (rs138375140, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MYOM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 569222). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYOM1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.61
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.036
T;.;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.087
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.90
N;.;N
PhyloP100
3.6
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.21
N;.;N
REVEL
Benign
0.15
Sift
Benign
0.049
D;.;T
Sift4G
Benign
0.52
T;T;T
Polyphen
0.85
P;.;P
Vest4
0.17
MVP
0.68
MPC
0.50
ClinPred
0.11
T
GERP RS
5.5
Varity_R
0.10
gMVP
0.39
Mutation Taster
=92/8
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs138375140; hg19: chr18-3168932; API