22-25761123-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_032608.7(MYO18B):​c.31G>T​(p.Glu11*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000422 in 1,613,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

MYO18B
NM_032608.7 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.75

Publications

1 publications found
Variant links:
Genes affected
MYO18B (HGNC:18150): (myosin XVIIIB) The protein encoded by this gene may regulate muscle-specific genes when in the nucleus and may influence intracellular trafficking when in the cytoplasm. The encoded protein functions as a homodimer and may interact with F actin. Mutations in this gene are associated with lung cancer. [provided by RefSeq, Jul 2008]
MYO18B Gene-Disease associations (from GenCC):
  • Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 102 pathogenic variants in the truncated region.
PP5
Variant 22-25761123-G-T is Pathogenic according to our data. Variant chr22-25761123-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1448838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO18BNM_032608.7 linkc.31G>T p.Glu11* stop_gained Exon 2 of 44 ENST00000335473.12 NP_115997.5 Q8IUG5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO18BENST00000335473.12 linkc.31G>T p.Glu11* stop_gained Exon 2 of 44 1 NM_032608.7 ENSP00000334563.8 Q8IUG5-1
MYO18BENST00000407587.6 linkc.31G>T p.Glu11* stop_gained Exon 2 of 44 1 ENSP00000386096.2 Q8IUG5-3
MYO18BENST00000536101.5 linkc.31G>T p.Glu11* stop_gained Exon 2 of 43 1 ENSP00000441229.1 Q8IUG5-1
MYO18BENST00000539302.5 linkn.31G>T non_coding_transcript_exon_variant Exon 1 of 42 1 ENSP00000437587.1 F5H6I8

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000603
AC:
15
AN:
248720
AF XY:
0.0000889
show subpopulations
Gnomad AFR exome
AF:
0.0000643
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000438
AC:
64
AN:
1461020
Hom.:
0
Cov.:
32
AF XY:
0.0000468
AC XY:
34
AN XY:
726848
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000255
AC:
22
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52738
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000351
AC:
39
AN:
1111858
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
4
7
11
14
18
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:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000601
Hom.:
0
Bravo
AF:
0.0000340
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Dec 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu11*) in the MYO18B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO18B are known to be pathogenic (PMID: 25748484, 32184166, 32637634). This variant is present in population databases (rs757976244, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYO18B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1448838). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
44
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.91
D
PhyloP100
5.8
Vest4
0.19
GERP RS
5.3
Mutation Taster
=15/185
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
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

Other links and lift over

dbSNP: rs757976244; hg19: chr22-26157090; API