NM_004468.5:c.299A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004468.5(FHL3):ā€‹c.299A>Gā€‹(p.Gln100Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,614,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00014 ( 0 hom., cov: 33)
Exomes š‘“: 0.000022 ( 0 hom. )

Consequence

FHL3
NM_004468.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11895248).
BS2
High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHL3NM_004468.5 linkc.299A>G p.Gln100Arg missense_variant Exon 3 of 6 ENST00000373016.4 NP_004459.2 Q13643
FHL3NM_001243878.2 linkc.-26A>G 5_prime_UTR_variant Exon 2 of 5 NP_001230807.1 Q13643Q96C98

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHL3ENST00000373016.4 linkc.299A>G p.Gln100Arg missense_variant Exon 3 of 6 1 NM_004468.5 ENSP00000362107.3 Q13643

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000434
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.0000637
AC:
16
AN:
251232
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461866
Hom.:
0
Cov.:
34
AF XY:
0.0000248
AC XY:
18
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152368
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74526
show subpopulations
Gnomad4 AFR
AF:
0.000433
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000141
Hom.:
0
Bravo
AF:
0.000200
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.299A>G (p.Q100R) alteration is located in exon 3 (coding exon 2) of the FHL3 gene. This alteration results from a A to G substitution at nucleotide position 299, causing the glutamine (Q) at amino acid position 100 to be replaced by an arginine (R). 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
0.071
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
18
DANN
Benign
0.27
DEOGEN2
Benign
0.0034
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
-1.0
N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
1.9
N
REVEL
Uncertain
0.40
Sift
Benign
0.77
T
Sift4G
Benign
1.0
T
Polyphen
0.0060
B
Vest4
0.43
MVP
0.62
MPC
0.34
ClinPred
0.041
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.29

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: rs137998324; hg19: chr1-38464678; API