NM_020840.3:c.134A>G

Variant names:

• chr4-158825942-A-G
• rs1778132432
• NM_020840.3:c.134A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020840.3(FNIP2):​c.134A>G​(p.Asn45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNIP2 NM_020840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026864588).

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.134A>G	p.Asn45Ser	missense	Exon 2 of 17	NP_065891.1	Q9P278-1
	FNIP2	NM_001366843.1		c.203A>G	p.Asn68Ser	missense	Exon 2 of 18	NP_001353772.1
	FNIP2	NM_001323916.2		c.203A>G	p.Asn68Ser	missense	Exon 2 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.134A>G	p.Asn45Ser	missense	Exon 2 of 17	ENSP00000264433.6	Q9P278-1
	FNIP2	ENST00000512986.5	TSL:1	c.203A>G	p.Asn68Ser	missense	Exon 2 of 13	ENSP00000421488.1	D6RFH5
	FNIP2	ENST00000504704.6	TSL:1	n.153A>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.056
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.9
DANN	Benign	0.24
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.42	N
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.057	B
Vest4		0.25
MutPred		0.19		Gain of disorder (P = 0.0414)
MVP		0.043
MPC		0.12
ClinPred		0.035	T
GERP RS		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.047
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1778132432; hg19: chr4-159747094;