rs764717219

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_014845.6(FIG4):c.759del(p.Phe254SerfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,612,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

FIG4
NM_014845.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 7.82

Variant links:

Genes affected

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

FIG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 6-109738434-TG-T is Pathogenic according to our data. Variant chr6-109738434-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 254668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109738434-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIG4	NM_014845.6 linkuse as main transcript	c.759del	p.Phe254SerfsTer8	frameshift_variant	7/23	ENST00000230124.8
FIG4	XM_011536281.4 linkuse as main transcript	c.696del	p.Phe233SerfsTer8	frameshift_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIG4	ENST00000230124.8 linkuse as main transcript	c.759del	p.Phe254SerfsTer8	frameshift_variant	7/23	1	NM_014845.6	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251044

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1460546

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	Identified by whole exome sequencing in the heterozygous state in an individual with ALS; however, the variant was identified in his unaffected father and other affected relatives were not available for molecular testing to establish segregation (Osmanovic et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28051077, 21705420, 17572665, 31589614, 32376792) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 14, 2017	- -

Charcot-Marie-Tooth disease type 4J

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 05, 2007	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Amyotrophic lateral sclerosis type 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Weber Lab, Hannover Medical School

Sep 13, 2016

- -

Charcot-Marie-Tooth disease type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change creates a premature translational stop signal (p.Phe254Serfs*8) in the FIG4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FIG4 are known to be pathogenic (PMID: 23623387, 30740813). This variant is present in population databases (rs764717219, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 17572665, 21705420). ClinVar contains an entry for this variant (Variation ID: 254668). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over