Menu
GeneBe

19-48757961-G-A

Variant summary

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

The NM_019113.4(FGF21):c.371G>A(p.Arg124Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,588,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

FGF21
NM_019113.4 missense

Scores

1
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.482
Variant links:
Genes affected
FGF21 (HGNC:3678): (fibroblast growth factor 21) Theis gene encodes a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. This protein is a secreted endocrine factor that functions as a major metabolic regulator. The encoded protein stimulates the uptake of glucose in adipose tissue. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.14916101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FGF21NM_019113.4 linkuse as main transcriptc.371G>A p.Arg124Gln missense_variant 4/4 ENST00000593756.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGF21ENST00000593756.6 linkuse as main transcriptc.371G>A p.Arg124Gln missense_variant 4/41 NM_019113.4 P1
FGF21ENST00000222157.5 linkuse as main transcriptc.371G>A p.Arg124Gln missense_variant 3/31 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000447
AC:
68
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00254
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000470
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000292
AC:
67
AN:
229542
Hom.:
0
AF XY:
0.000322
AC XY:
40
AN XY:
124382
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000257
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000966
Gnomad NFE exome
AF:
0.000337
Gnomad OTH exome
AF:
0.000729
GnomAD4 exome
AF:
0.000510
AC:
733
AN:
1436162
Hom.:
0
Cov.:
31
AF XY:
0.000504
AC XY:
359
AN XY:
712800
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.000194
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000987
Gnomad4 NFE exome
AF:
0.000582
Gnomad4 OTH exome
AF:
0.000541
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000447
AC:
68
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.000552
AC XY:
41
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00254
Gnomad4 NFE
AF:
0.000470
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000393
Hom.:
0
Bravo
AF:
0.000261
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000272
AC:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 07, 2022The c.371G>A (p.R124Q) alteration is located in exon 3 (coding exon 3) of the FGF21 gene. This alteration results from a G to A substitution at nucleotide position 371, causing the arginine (R) at amino acid position 124 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
0.086
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.27
Cadd
Benign
22
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.61
D;D
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Benign
0.58
D
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Uncertain
-0.027
T
MutationAssessor
Uncertain
2.6
M;M
MutationTaster
Benign
0.90
D
PrimateAI
Benign
0.37
T
Sift4G
Uncertain
0.057
T;T
Polyphen
0.96
D;D
Vest4
0.25
MVP
0.92
MPC
0.070
ClinPred
0.10
T
GERP RS
3.4
Varity_R
0.064
gMVP
0.47

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: rs142980324; hg19: chr19-49261218; COSMIC: COSV99711465; COSMIC: COSV99711465; API