1-37998126-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_004468.5(FHL3):​c.338G>A​(p.Arg113Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,856 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: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FHL3
NM_004468.5 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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 -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.813
BS2
High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHL3NM_004468.5 linkc.338G>A p.Arg113Gln missense_variant Exon 4 of 6 ENST00000373016.4 NP_004459.2 Q13643
FHL3NM_001243878.2 linkc.14G>A p.Arg5Gln missense_variant Exon 3 of 5 NP_001230807.1 Q13643Q96C98

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHL3ENST00000373016.4 linkc.338G>A p.Arg113Gln missense_variant Exon 4 of 6 1 NM_004468.5 ENSP00000362107.3 Q13643
FHL3ENST00000485803.5 linkn.328G>A non_coding_transcript_exon_variant Exon 3 of 5 1
FHL3ENST00000477194.5 linkn.526G>A non_coding_transcript_exon_variant Exon 4 of 6 2
FHL3ENST00000475084.5 linkn.322-256G>A intron_variant Intron 2 of 3 5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250906
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135706
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461720
Hom.:
0
Cov.:
34
AF XY:
0.0000124
AC XY:
9
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Bravo
AF:
0.0000113
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
Mar 02, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.338G>A (p.R113Q) alteration is located in exon 4 (coding exon 3) of the FHL3 gene. This alteration results from a G to A substitution at nucleotide position 338, causing the arginine (R) at amino acid position 113 to be replaced by a glutamine (Q). 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
0.34
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.29
T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.7
D
REVEL
Pathogenic
0.71
Sift
Benign
0.31
T
Sift4G
Benign
0.13
T
Polyphen
1.0
D
Vest4
0.83
MutPred
0.55
Gain of ubiquitination at K114 (P = 0.078);
MVP
0.87
MPC
1.1
ClinPred
0.94
D
GERP RS
5.2
Varity_R
0.46
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs771932815; hg19: chr1-38463798; API