5-131651917-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133372.3(FNIP1):c.3191G>C(p.Ser1064Thr) variant causes a missense change involving the alteration of a 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)
• Consequence: FNIP1 NM_133372.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNIP1	NM_133372.3	c.3191G>C	p.Ser1064Thr	missense_variant	16/18	ENST00000510461.6
FNIP1	NM_001008738.3	c.3107G>C	p.Ser1036Thr	missense_variant	15/17
FNIP1	NM_001346114.2	c.3056G>C	p.Ser1019Thr	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNIP1	ENST00000510461.6	c.3191G>C	p.Ser1064Thr	missense_variant	16/18	1	NM_133372.3	P4
FNIP1	ENST00000307954.12	c.3056G>C	p.Ser1019Thr	missense_variant	15/17	1
FNIP1	ENST00000307968.11	c.3107G>C	p.Ser1036Thr	missense_variant	15/17	5		A1

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.3191G>C (p.S1064T) alteration is located in exon 16 (coding exon 16) of the FNIP1 gene. This alteration results from a G to C substitution at nucleotide position 3191, causing the serine (S) at amino acid position 1064 to be replaced by a threonine (T). 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	Benign	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Uncertain	-2.7	D;D;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.99	D;.;.;D
Vest4		0.81
MutPred		0.56		.;.;.;Gain of phosphorylation at S1064 (P = 0.068);
MVP		0.14
MPC		0.34
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1767050563; hg19: chr5-130987610;