1-37997859-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004468.5(FHL3):ā€‹c.513G>Cā€‹(p.Gln171His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

FHL3
NM_004468.5 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49
Variant links:
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35284868).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHL3NM_004468.5 linkc.513G>C p.Gln171His missense_variant Exon 5 of 6 ENST00000373016.4 NP_004459.2 Q13643
FHL3NM_001243878.2 linkc.189G>C p.Gln63His missense_variant Exon 4 of 5 NP_001230807.1 Q13643Q96C98

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHL3ENST00000373016.4 linkc.513G>C p.Gln171His missense_variant Exon 5 of 6 1 NM_004468.5 ENSP00000362107.3 Q13643
FHL3ENST00000485803.5 linkn.503G>C non_coding_transcript_exon_variant Exon 4 of 5 1
FHL3ENST00000475084.5 linkn.333G>C non_coding_transcript_exon_variant Exon 3 of 4 5
FHL3ENST00000477194.5 linkn.701G>C non_coding_transcript_exon_variant Exon 5 of 6 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251172
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135758
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461502
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.513G>C (p.Q171H) alteration is located in exon 5 (coding exon 4) of the FHL3 gene. This alteration results from a G to C substitution at nucleotide position 513, causing the glutamine (Q) at amino acid position 171 to be replaced by a histidine (H). 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
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.35
T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
0.83
L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.42
Sift
Benign
0.037
D
Sift4G
Uncertain
0.020
D
Polyphen
0.98
D
Vest4
0.36
MutPred
0.52
Loss of MoRF binding (P = 0.1159);
MVP
0.76
MPC
0.87
ClinPred
0.76
D
GERP RS
4.3
Varity_R
0.25
gMVP
0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs775200045; hg19: chr1-38463531; API