4-158859585-T-A

Variant names:

• chr4-158859585-T-A
• rs368957383
• NM_020840.3:c.1067T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020840.3(FNIP2):​c.1067T>A​(p.Ile356Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 3.77
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35712564).

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.1067T>A	p.Ile356Asn	missense	Exon 10 of 17	NP_065891.1	Q9P278-1
	FNIP2	NM_001366843.1		c.1226T>A	p.Ile409Asn	missense	Exon 11 of 18	NP_001353772.1
	FNIP2	NM_001323916.2		c.1136T>A	p.Ile379Asn	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.1067T>A	p.Ile356Asn	missense	Exon 10 of 17	ENSP00000264433.6	Q9P278-1
	FNIP2	ENST00000512986.5	TSL:1	c.1136T>A	p.Ile379Asn	missense	Exon 10 of 13	ENSP00000421488.1	D6RFH5
	FNIP2	ENST00000956831.1		c.1148T>A	p.Ile383Asn	missense	Exon 11 of 18	ENSP00000626890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.023	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.78
MutPred		0.28		Gain of glycosylation at S357 (P = 0.0181)
MVP		0.10
MPC		0.77
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.74
Mutation Taster		=39/61	disease causing

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: rs368957383; hg19: chr4-159780737;