5-131651956-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_133372.3(FNIP1):c.3152T>C(p.Ile1051Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: FNIP1 NM_133372.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

FNIP1 (HGNC:29418): (folliculin interacting protein 1) This gene encodes a protein that binds to the tumor suppressor protein folliculin and to AMP-activated protein kinase (AMPK). The encoded protein participates in the regulation of cellular metabolism and nutrient sensing by modulating the AMPK and target of rapamycin signaling pathways. 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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000854 (13/152252) while in subpopulation NFE AF= 0.000176 (12/68038). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNIP1	NM_133372.3	c.3152T>C	p.Ile1051Thr	missense_variant	16/18	ENST00000510461.6
FNIP1	NM_001008738.3	c.3068T>C	p.Ile1023Thr	missense_variant	15/17
FNIP1	NM_001346114.2	c.3017T>C	p.Ile1006Thr	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNIP1	ENST00000510461.6	c.3152T>C	p.Ile1051Thr	missense_variant	16/18	1	NM_133372.3	P4
FNIP1	ENST00000307954.12	c.3017T>C	p.Ile1006Thr	missense_variant	15/17	1
FNIP1	ENST00000307968.11	c.3068T>C	p.Ile1023Thr	missense_variant	15/17	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251220 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74390

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1051 of the FNIP1 protein (p.Ile1051Thr). This variant is present in population databases (rs371264668, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FNIP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Uncertain	-4.0	D;D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.91	P;.;.;D
Vest4		0.92
MVP		0.13
MPC		0.39
ClinPred		0.54	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371264668; hg19: chr5-130987649;