rs122458143
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_001159702.3(FHL1):c.395G>T(p.Cys132Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
FHL1
NM_001159702.3 missense
NM_001159702.3 missense
Scores
9
2
1
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
FHL1 (HGNC:3702): (four and a half LIM domains 1) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a domain LIM zinc-binding 2 (size 52) in uniprot entity FHL1_HUMAN there are 24 pathogenic changes around while only 1 benign (96%) in NM_001159702.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
?
Variant X-136207855-G-T is Pathogenic according to our data. Variant chrX-136207855-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11551.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136207855-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FHL1 | NM_001159702.3 | c.395G>T | p.Cys132Phe | missense_variant | 5/8 | ENST00000394155.8 | |
FHL1 | NM_001159699.2 | c.443G>T | p.Cys148Phe | missense_variant | 4/6 | ENST00000370683.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FHL1 | ENST00000394155.8 | c.395G>T | p.Cys132Phe | missense_variant | 5/8 | 5 | NM_001159702.3 | ||
FHL1 | ENST00000370683.6 | c.443G>T | p.Cys148Phe | missense_variant | 4/6 | 1 | NM_001159699.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myopathy, reducing body, X-linked, early-onset, severe Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2008 | - - |
Centronuclear myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PS1+PM1+PM2+PP3+PP4+PP5 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;H
MutationTaster
Benign
A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.
Vest4
MutPred
Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);.;.;.;Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);
MVP
MPC
1.7
ClinPred
D
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at