chr4-158859136-A-C

Variant names:

• chr4-158859136-A-C
• rs1194280553
• NM_020840.3:c.937A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020840.3(FNIP2):​c.937A>C​(p.Ile313Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I313V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FNIP2 NM_020840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.20
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21364683).

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.937A>C	p.Ile313Leu	missense	Exon 9 of 17	NP_065891.1	Q9P278-1
	FNIP2	NM_001366843.1		c.1096A>C	p.Ile366Leu	missense	Exon 10 of 18	NP_001353772.1
	FNIP2	NM_001323916.2		c.1006A>C	p.Ile336Leu	missense	Exon 9 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.937A>C	p.Ile313Leu	missense	Exon 9 of 17	ENSP00000264433.6	Q9P278-1
	FNIP2	ENST00000512986.5	TSL:1	c.1006A>C	p.Ile336Leu	missense	Exon 9 of 13	ENSP00000421488.1	D6RFH5
	FNIP2	ENST00000956831.1		c.1018A>C	p.Ile340Leu	missense	Exon 10 of 18	ENSP00000626890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.047
Sift	Benign	0.14	T
Sift4G	Benign	0.11	T
Polyphen		0.19	B
Vest4		0.35
MutPred		0.68		Loss of sheet (P = 0.0457)
MVP		0.043
MPC		0.18
ClinPred		0.40	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.72
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: rs1194280553; hg19: chr4-159780288;