4-158859639-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020840.3(FNIP2):​c.1121G>A​(p.Arg374His) variant causes a missense change. The variant allele was found at a frequency of 0.000545 in 1,613,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

FNIP2
NM_020840.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.32
Variant links:
Genes affected
FNIP2 (HGNC:29280): (folliculin interacting protein 2) This gene encodes a protein that binds to the tumor suppressor folliculin and to AMP-activated protein kinase (AMPK), and may play a role cellular metabolism and nutrient sensing by regulating the AMPK-mechanistic target of rapamycin signaling pathway. The encoded protein may also be involved in regulating the O6-methylguanine-induced apoptosis signaling pathway. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin. [provided by RefSeq, Jul 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.014872372).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FNIP2NM_020840.3 linkuse as main transcriptc.1121G>A p.Arg374His missense_variant 10/17 ENST00000264433.11 NP_065891.1 Q9P278-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FNIP2ENST00000264433.11 linkuse as main transcriptc.1121G>A p.Arg374His missense_variant 10/171 NM_020840.3 ENSP00000264433.6 Q9P278-1
FNIP2ENST00000512986.5 linkuse as main transcriptc.1190G>A p.Arg397His missense_variant 10/131 ENSP00000421488.1 D6RFH5
FNIP2ENST00000504715.1 linkuse as main transcriptc.716G>A p.Arg239His missense_variant 7/75 ENSP00000420841.1 H0Y8F3

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000515
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000427
AC:
106
AN:
248260
Hom.:
0
AF XY:
0.000453
AC XY:
61
AN XY:
134650
show subpopulations
Gnomad AFR exome
AF:
0.000195
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.00132
Gnomad FIN exome
AF:
0.000279
Gnomad NFE exome
AF:
0.000409
Gnomad OTH exome
AF:
0.000664
GnomAD4 exome
AF:
0.000558
AC:
815
AN:
1461072
Hom.:
0
Cov.:
31
AF XY:
0.000523
AC XY:
380
AN XY:
726774
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00125
Gnomad4 FIN exome
AF:
0.000469
Gnomad4 NFE exome
AF:
0.000564
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.000524
AC XY:
39
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00208
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000515
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000379
Hom.:
0
Bravo
AF:
0.000476
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000267
AC:
1
ESP6500EA
AF:
0.000727
AC:
6
ExAC
AF:
0.000430
AC:
52
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000238

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 GeneticsMar 01, 2024The c.1121G>A (p.R374H) alteration is located in exon 10 (coding exon 10) of the FNIP2 gene. This alteration results from a G to A substitution at nucleotide position 1121, causing the arginine (R) at amino acid position 374 to be replaced by a histidine (H). 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
0.077
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;T;.
Eigen
Benign
-0.095
Eigen_PC
Benign
-0.0060
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.015
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
M;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Benign
0.086
Sift
Benign
0.045
D;T;D
Sift4G
Uncertain
0.043
D;D;T
Polyphen
0.35
B;.;.
Vest4
0.36
MVP
0.043
MPC
0.18
ClinPred
0.031
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs199995620; hg19: chr4-159780791; API