4-158904486-C-T

Variant names:

• chr4-158904486-C-T
• NM_020840.3:c.3287C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020840.3(FNIP2):​c.3287C>T​(p.Pro1096Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FNIP2 NM_020840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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]

SPMIP2 (HGNC:26342): (sperm microtubule inner protein 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

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.3287C>T	p.Pro1096Leu	missense	Exon 17 of 17	NP_065891.1	Q9P278-1
	SPMIP2	NM_152543.3	MANE Select	c.546+10684G>A		intron	N/A	NP_689756.2	Q96LM5
	FNIP2	NM_001366843.1		c.3446C>T	p.Pro1149Leu	missense	Exon 18 of 18	NP_001353772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNIP2	ENST00000264433.11	TSL:1 MANE Select	c.3287C>T	p.Pro1096Leu	missense	Exon 17 of 17	ENSP00000264433.6	Q9P278-1
	SPMIP2	ENST00000434826.3	TSL:2 MANE Select	c.546+10684G>A		intron	N/A	ENSP00000412215.2	Q96LM5
	FNIP2	ENST00000956831.1		c.3368C>T	p.Pro1123Leu	missense	Exon 18 of 18	ENSP00000626890.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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	0.71
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.55		Gain of helix (P = 0.062)
MVP		0.13
MPC		0.63
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.80
Mutation Taster		=33/67	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

hg19: chr4-159825638;