chr4-158859639-G-A

Position:

• chr4-158859639-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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]

ACMG classification

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
FNIP2	NM_020840.3	c.1121G>A	p.Arg374His	missense_variant	10/17	ENST00000264433.11	NP_065891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNIP2	ENST00000264433.11	c.1121G>A	p.Arg374His	missense_variant	10/17	1	NM_020840.3	ENSP00000264433.6
FNIP2	ENST00000512986.5	c.1190G>A	p.Arg397His	missense_variant	10/13	1		ENSP00000421488.1
FNIP2	ENST00000504715.1	c.716G>A	p.Arg239His	missense_variant	7/7	5		ENSP00000420841.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152120 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The 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

Other links and lift over

dbSNP: rs199995620; hg19: chr4-159780791;