4-158861662-A-G

Variant names:

• chr4-158861662-A-G
• rs765081062
• NM_020840.3:c.1351A>G

Variant summary

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

The NM_020840.3(FNIP2):​c.1351A>G​(p.Thr451Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FNIP2 NM_020840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

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.1351A>G	p.Thr451Ala	missense	Exon 12 of 17	NP_065891.1	Q9P278-1
	FNIP2	NM_001366843.1		c.1510A>G	p.Thr504Ala	missense	Exon 13 of 18	NP_001353772.1
	FNIP2	NM_001323916.2		c.1420A>G	p.Thr474Ala	missense	Exon 12 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.1351A>G	p.Thr451Ala	missense	Exon 12 of 17	ENSP00000264433.6	Q9P278-1
	FNIP2	ENST00000512986.5	TSL:1	c.1420A>G	p.Thr474Ala	missense	Exon 12 of 13	ENSP00000421488.1	D6RFH5
	FNIP2	ENST00000956831.1		c.1432A>G	p.Thr478Ala	missense	Exon 13 of 18	ENSP00000626890.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249254 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727136

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: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111868

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.21
MPC		0.62
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.69
gMVP		0.82
Mutation Taster		=40/60	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: rs765081062; hg19: chr4-159782814;