1-37998115-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_004468.5(FHL3):c.349T>C(p.Tyr117His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,776 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FHL3
NM_004468.5 missense
NM_004468.5 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 6.25
Genes affected
FHL3 (HGNC:3704): (four and a half LIM domains 3) The protein encoded by this gene is a member of a family of proteins containing a four-and-a-half LIM domain, which is a highly conserved double zinc finger motif. The encoded protein has been shown to interact with the cancer developmental regulators SMAD2, SMAD3, and SMAD4, the skeletal muscle myogenesis protein MyoD, and the high-affinity IgE beta chain regulator MZF-1. This protein may be involved in tumor suppression, repression of MyoD expression, and repression of IgE receptor expression. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
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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, 0.844
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FHL3 | NM_004468.5 | c.349T>C | p.Tyr117His | missense_variant | 4/6 | ENST00000373016.4 | |
FHL3 | NM_001243878.2 | c.25T>C | p.Tyr9His | missense_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FHL3 | ENST00000373016.4 | c.349T>C | p.Tyr117His | missense_variant | 4/6 | 1 | NM_004468.5 | P1 | |
FHL3 | ENST00000485803.5 | n.339T>C | non_coding_transcript_exon_variant | 3/5 | 1 | ||||
FHL3 | ENST00000477194.5 | n.537T>C | non_coding_transcript_exon_variant | 4/6 | 2 | ||||
FHL3 | ENST00000475084.5 | n.322-245T>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461776Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727196
GnomAD4 exome
AF:
AC:
1
AN:
1461776
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
727196
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
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 submitter | clinical testing | Ambry Genetics | Aug 13, 2021 | The c.349T>C (p.Y117H) alteration is located in exon 4 (coding exon 3) of the FHL3 gene. This alteration results from a T to C substitution at nucleotide position 349, causing the tyrosine (Y) at amino acid position 117 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0174);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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