chr5-131651819-T-C

Position:

• chr5-131651819-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133372.3(FNIP1):​c.3289A>G​(p.Asn1097Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNIP1 NM_133372.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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]

ENSG00000273217 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNIP1	NM_133372.3	c.3289A>G	p.Asn1097Asp	missense_variant	16/18	ENST00000510461.6	NP_588613.3
FNIP1	NM_001008738.3	c.3205A>G	p.Asn1069Asp	missense_variant	15/17		NP_001008738.3
FNIP1	NM_001346114.2	c.3154A>G	p.Asn1052Asp	missense_variant	15/17		NP_001333043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNIP1	ENST00000510461.6	c.3289A>G	p.Asn1097Asp	missense_variant	16/18	1	NM_133372.3	ENSP00000421985.1
FNIP1	ENST00000307954.12	c.3154A>G	p.Asn1052Asp	missense_variant	15/17	1		ENSP00000310453.8
ENSG00000273217	ENST00000514667.1	c.220-47126A>G		intron_variant		2		ENSP00000426948.1
FNIP1	ENST00000307968.11	c.3205A>G	p.Asn1069Asp	missense_variant	15/17	5		ENSP00000309266.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 06, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FNIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1097 of the FNIP1 protein (p.Asn1097Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	.;.;.;M
PROVEAN	Uncertain	-2.6	D;D;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.025	D;D;.;D
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		0.99	D;.;.;D
Vest4		0.74
MutPred		0.35		.;.;.;Loss of methylation at K1095 (P = 0.1181);
MVP		0.082
MPC		2.6
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-130987512;