NM_020840.3:c.1121G>A

Variant names:

• chr4-158859639-G-A
• rs199995620
• NM_020840.3:c.1121G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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
• Publications: 5 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014872372).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020840.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNIP2	NM_020840.3	MANE Select	c.1121G>A	p.Arg374His	missense	Exon 10 of 17	NP_065891.1	Q9P278-1
	FNIP2	NM_001366843.1		c.1280G>A	p.Arg427His	missense	Exon 11 of 18	NP_001353772.1
	FNIP2	NM_001323916.2		c.1190G>A	p.Arg397His	missense	Exon 10 of 17	NP_001310845.1	Q9P278-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNIP2	ENST00000264433.11	TSL:1 MANE Select	c.1121G>A	p.Arg374His	missense	Exon 10 of 17	ENSP00000264433.6	Q9P278-1
	FNIP2	ENST00000512986.5	TSL:1	c.1190G>A	p.Arg397His	missense	Exon 10 of 13	ENSP00000421488.1	D6RFH5
	FNIP2	ENST00000956831.1		c.1202G>A	p.Arg401His	missense	Exon 11 of 18	ENSP00000626890.1

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

GnomAD2 exomes AF: 0.000427 AC: 106 AN: 248260 AF XY: 0.000453

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.000179 AC: 8 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86064

European-Finnish (FIN) AF: 0.000469 AC: 25 AN: 53350

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000564 AC: 627 AN: 1111584

Other (OTH) AF: 0.000679 AC: 41 AN: 60350

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74430

African (AFR) AF: 0.000169 AC: 7 AN: 41538

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68012

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000409 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.0060
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.086
Sift	Benign	0.045	D
Sift4G	Uncertain	0.043	D
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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs199995620; hg19: chr4-159780791;