5-131647140-G-T

Position:

• chr5-131647140-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_133372.3(FNIP1):​c.3372C>A​(p.Tyr1124*) variant causes a stop gained 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNIP1 NM_133372.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.449

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0368 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-131647140-G-T is Pathogenic according to our data. Variant chr5-131647140-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3670425.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNIP1	NM_133372.3	c.3372C>A	p.Tyr1124*	stop_gained	17/18	ENST00000510461.6	NP_588613.3
FNIP1	NM_001008738.3	c.3288C>A	p.Tyr1096*	stop_gained	16/17		NP_001008738.3
FNIP1	NM_001346114.2	c.3237C>A	p.Tyr1079*	stop_gained	16/17		NP_001333043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNIP1	ENST00000510461.6	c.3372C>A	p.Tyr1124*	stop_gained	17/18	1	NM_133372.3	ENSP00000421985.1
FNIP1	ENST00000307954.12	c.3237C>A	p.Tyr1079*	stop_gained	16/17	1		ENSP00000310453.8
ENSG00000273217	ENST00000514667.1	c.220-42447C>A		intron_variant		2		ENSP00000426948.1
FNIP1	ENST00000307968.11	c.3288C>A	p.Tyr1096*	stop_gained	16/17	5		ENSP00000309266.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2024

This sequence change creates a premature translational stop signal (p.Tyr1124*) in the FNIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FNIP1 are known to be pathogenic (PMID: 32181500, 32905580). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FNIP1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.47
GERP RS		-0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -50

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: chr5-130982833;