rs146125558
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_001159702.3(FHL1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,210,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.
Frequency
Consequence
NM_001159702.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FHL1 | NM_001159702.3 | c.5C>T | p.Ala2Val | missense_variant | 3/8 | ENST00000394155.8 | |
FHL1 | NM_001159699.2 | c.53C>T | p.Ala18Val | missense_variant | 2/6 | ENST00000370683.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FHL1 | ENST00000394155.8 | c.5C>T | p.Ala2Val | missense_variant | 3/8 | 5 | NM_001159702.3 | ||
FHL1 | ENST00000370683.6 | c.53C>T | p.Ala18Val | missense_variant | 2/6 | 1 | NM_001159699.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000445 AC: 5AN: 112482Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34640
GnomAD3 exomes AF: 0.0000327 AC: 6AN: 183451Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67887
GnomAD4 exome AF: 0.0000219 AC: 24AN: 1098228Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8AN XY: 363582
GnomAD4 genome ? AF: 0.0000445 AC: 5AN: 112482Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 34640
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 02, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2021 | Has not been previously published as pathogenic or benign to our knowledge - |
X-linked myopathy with postural muscle atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the FHL1 protein (p.Ala2Val). This variant is present in population databases (rs146125558, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 289087). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2021 | The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the FHL1 gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (6/183451) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was <0.01% (1/13161) of African alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at