18-3079331-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003803.4(MYOM1):​c.4496T>A​(p.Ile1499Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

7
9
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.66
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYOM1NM_003803.4 linkc.4496T>A p.Ile1499Asn missense_variant 34/38 ENST00000356443.9 NP_003794.3 P52179-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYOM1ENST00000356443.9 linkc.4496T>A p.Ile1499Asn missense_variant 34/381 NM_003803.4 ENSP00000348821.4 P52179-1
MYOM1ENST00000261606.11 linkc.4208T>A p.Ile1403Asn missense_variant 33/371 ENSP00000261606.7 P52179-2
MYOM1ENST00000581075.1 linkn.*142T>A non_coding_transcript_exon_variant 7/85 ENSP00000462039.1 J3KRK2
MYOM1ENST00000581075.1 linkn.*142T>A 3_prime_UTR_variant 7/85 ENSP00000462039.1 J3KRK2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247722
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134338
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1457476
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
724406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Benign
-0.53
T
MutationAssessor
Pathogenic
2.9
M;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-6.0
D;.;D
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.85
MutPred
0.60
Gain of disorder (P = 0.005);.;.;
MVP
0.68
MPC
0.66
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.89
gMVP
0.89

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.

Other links and lift over

dbSNP: rs1060502820; hg19: chr18-3079329; API