5-131647188-T-G

Position:

• chr5-131647188-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_133372.3(FNIP1):​c.3324A>C​(p.Glu1108Asp) variant causes a missense change involving the alteration of a non-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: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FNIP1 NM_133372.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.453

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNIP1	NM_133372.3	c.3324A>C	p.Glu1108Asp	missense_variant	17/18	ENST00000510461.6	NP_588613.3
FNIP1	NM_001008738.3	c.3240A>C	p.Glu1080Asp	missense_variant	16/17		NP_001008738.3
FNIP1	NM_001346114.2	c.3189A>C	p.Glu1063Asp	missense_variant	16/17		NP_001333043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNIP1	ENST00000510461.6	c.3324A>C	p.Glu1108Asp	missense_variant	17/18	1	NM_133372.3	ENSP00000421985.1
FNIP1	ENST00000307954.12	c.3189A>C	p.Glu1063Asp	missense_variant	16/17	1		ENSP00000310453.8
ENSG00000273217	ENST00000514667.1	c.220-42495A>C		intron_variant		2		ENSP00000426948.1
FNIP1	ENST00000307968.11	c.3240A>C	p.Glu1080Asp	missense_variant	16/17	5		ENSP00000309266.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000251 AC: 366 AN: 1457990 Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 168 AN XY: 725404

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2024

The c.3324A>C (p.E1108D) alteration is located in exon 17 (coding exon 17) of the FNIP1 gene. This alteration results from a A to C substitution at nucleotide position 3324, causing the glutamic acid (E) at amino acid position 1108 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	.;.;.;M
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.95
MutPred		0.77		.;.;.;Loss of helix (P = 0.1299);
MVP		0.48
MPC		2.4
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-130982881;