4-189960773-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004477.3(FRG1):​c.563C>T​(p.Thr188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,607,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FRG1
NM_004477.3 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19
Variant links:
Genes affected
FRG1 (HGNC:3954): (FSHD region gene 1) This gene maps to a location 100 kb centromeric of the repeat units on chromosome 4q35 which are deleted in facioscapulohumeral muscular dystrophy (FSHD). It is evolutionarily conserved and has related sequences on multiple human chromosomes but DNA sequence analysis did not reveal any homology to known genes. In vivo studies demonstrate the encoded protein is localized to the nucleolus. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22380021).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRG1NM_004477.3 linkc.563C>T p.Thr188Ile missense_variant Exon 7 of 9 ENST00000226798.9 NP_004468.1 Q14331
FRG1XM_017007958.2 linkc.179C>T p.Thr60Ile missense_variant Exon 3 of 5 XP_016863447.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRG1ENST00000226798.9 linkc.563C>T p.Thr188Ile missense_variant Exon 7 of 9 1 NM_004477.3 ENSP00000226798.4 Q14331
FRG1ENST00000524583.5 linkc.179C>T p.Thr60Ile missense_variant Exon 6 of 7 5 ENSP00000435067.1 E9PLY7
FRG1ENST00000507103.1 linkn.26C>T non_coding_transcript_exon_variant Exon 1 of 4 3 ENSP00000462603.1 J3KSQ7
FRG1ENST00000514482.1 linkn.524-89C>T intron_variant Intron 6 of 6 3

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151810
Hom.:
0
Cov.:
33
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
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1455754
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
2
AN XY:
724298
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151810
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74128
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
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.563C>T (p.T188I) alteration is located in exon 7 (coding exon 7) of the FRG1 gene. This alteration results from a C to T substitution at nucleotide position 563, causing the threonine (T) at amino acid position 188 to be replaced by an isoleucine (I). 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
0.098
BayesDel_addAF
Benign
-0.0034
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.099
T;.
Eigen
Benign
-0.0059
Eigen_PC
Benign
0.091
FATHMM_MKL
Benign
0.71
D
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.99
T
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.11
Sift
Benign
0.13
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.17
B;.
Vest4
0.14
MutPred
0.28
Loss of phosphorylation at T188 (P = 0.0171);.;
MVP
0.54
MPC
0.56
ClinPred
0.59
D
GERP RS
4.0
Varity_R
0.16
gMVP
0.11

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs7440485; hg19: chr4-190881928; API