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GeneBe

12-109397751-C-T

Variant summary

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

The NM_001101421.4(MYO1H):c.509C>T(p.Thr170Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000922 in 1,611,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00054 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00096 ( 0 hom. )

Consequence

MYO1H
NM_001101421.4 missense

Scores

10
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
MYO1H (HGNC:13879): (myosin IH) Predicted to enable actin filament binding activity and microfilament motor activity. Predicted to be involved in actin filament organization and vesicle transport along actin filament. Predicted to be part of myosin complex. Predicted to be active in several cellular components, including actin cytoskeleton; microvillus; and vesicle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYO1HNM_001101421.4 linkuse as main transcriptc.509C>T p.Thr170Met missense_variant 5/32 ENST00000310903.10
MYO1HXM_011538223.3 linkuse as main transcriptc.461C>T p.Thr154Met missense_variant 6/34
MYO1HXM_047428738.1 linkuse as main transcriptc.461C>T p.Thr154Met missense_variant 4/31

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYO1HENST00000310903.10 linkuse as main transcriptc.509C>T p.Thr170Met missense_variant 5/325 NM_001101421.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000539
AC:
82
AN:
152106
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000985
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000566
AC:
140
AN:
247198
Hom.:
0
AF XY:
0.000574
AC XY:
77
AN XY:
134114
show subpopulations
Gnomad AFR exome
AF:
0.000324
Gnomad AMR exome
AF:
0.000325
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000264
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.000997
Gnomad OTH exome
AF:
0.000502
GnomAD4 exome
AF:
0.000962
AC:
1404
AN:
1459384
Hom.:
0
Cov.:
29
AF XY:
0.000919
AC XY:
667
AN XY:
725990
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000293
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000210
Gnomad4 FIN exome
AF:
0.0000937
Gnomad4 NFE exome
AF:
0.00118
Gnomad4 OTH exome
AF:
0.000846
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000539
AC:
82
AN:
152224
Hom.:
1
Cov.:
31
AF XY:
0.000497
AC XY:
37
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000985
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000870
Hom.:
0
Bravo
AF:
0.000540
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000480
AC:
4
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000554
AC:
67
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00132
EpiControl
AF:
0.00107

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 14, 2023The c.461C>T (p.T154M) alteration is located in exon 4 (coding exon 4) of the MYO1H gene. This alteration results from a C to T substitution at nucleotide position 461, causing the threonine (T) at amino acid position 154 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
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.40
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Benign
0.083
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
REVEL
Pathogenic
0.90
Sift4G
Pathogenic
0.0
D;D
Vest4
0.98
MVP
0.89
MPC
0.47
ClinPred
0.26
T
GERP RS
4.9
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs200839067; hg19: chr12-109835556; COSMIC: COSV60443095; COSMIC: COSV60443095; API