chr5-131644764-C-A

Variant names:

• chr5-131644764-C-A
• NM_133372.3:c.3423-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_133372.3(FNIP1):​c.3423-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FNIP1 NM_133372.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

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]

FNIP1 Gene-Disease associations (from GenCC):

• FNIP1-associated syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• immunodeficiency 93 and hypertrophic cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000273217 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133372.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNIP1	NM_133372.3	MANE Select	c.3423-1G>T		splice_acceptor intron	N/A	NP_588613.3	Q8TF40-1
	FNIP1	NM_001008738.3		c.3339-1G>T		splice_acceptor intron	N/A	NP_001008738.3	Q8TF40-3
	FNIP1	NM_001346114.2		c.3288-1G>T		splice_acceptor intron	N/A	NP_001333043.1	J3KNG8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNIP1	ENST00000510461.6	TSL:1 MANE Select	c.3423-1G>T		splice_acceptor intron	N/A	ENSP00000421985.1	Q8TF40-1
	ENSG00000273217	ENST00000514667.1	TSL:2	c.220-40071G>T		intron	N/A	ENSP00000426948.1	E9PCH4
	FNIP1	ENST00000307954.12	TSL:1	c.3288-1G>T		splice_acceptor intron	N/A	ENSP00000310453.8	J3KNG8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.92		Position offset: -1

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

Other links and lift over

hg19: chr5-130980457; COSMIC: COSV57195513;