rs375305856

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_004468.5(FHL3):ā€‹c.482G>Cā€‹(p.Arg161Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161H) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

FHL3
NM_004468.5 missense

Scores

6
11
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.41
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 -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.884
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHL3NM_004468.5 linkc.482G>C p.Arg161Pro missense_variant Exon 4 of 6 ENST00000373016.4 NP_004459.2 Q13643
FHL3NM_001243878.2 linkc.158G>C p.Arg53Pro 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.482G>C p.Arg161Pro missense_variant Exon 4 of 6 1 NM_004468.5 ENSP00000362107.3 Q13643
FHL3ENST00000485803.5 linkn.472G>C non_coding_transcript_exon_variant Exon 3 of 5 1
FHL3ENST00000477194.5 linkn.670G>C non_coding_transcript_exon_variant Exon 4 of 6 2
FHL3ENST00000475084.5 linkn.322-112G>C intron_variant Intron 2 of 3 5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00000398
AC:
1
AN:
251392
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461848
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000151
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.010
D
Sift4G
Uncertain
0.060
T
Polyphen
1.0
D
Vest4
0.88
MutPred
0.59
Gain of catalytic residue at P160 (P = 0.0133);
MVP
0.92
MPC
1.3
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.88
gMVP
0.87

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: rs375305856; hg19: chr1-38463654; COSMIC: COSV65952270; COSMIC: COSV65952270; API