6-109743725-A-T

Position:

chr6-109743725-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000230124.8(FIG4):c.1090A>T(p.Met364Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,612,658 control chromosomes in the GnomAD database, including 3,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.052 ( 405 hom., cov: 32)

Exomes 𝑓: 0.050 ( 3471 hom. )

Consequence

FIG4
ENST00000230124.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 8.93

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:

FIG4 (HGNC:):

FIG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016498268).

BP6

Variant 6-109743725-A-T is Benign according to our data. Variant chr6-109743725-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 137375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109743725-A-T is described in Lovd as [Benign]. Variant chr6-109743725-A-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIG4	NM_014845.6 linkuse as main transcript	c.1090A>T	p.Met364Leu	missense_variant	10/23	ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 linkuse as main transcript	c.1027A>T	p.Met343Leu	missense_variant	10/23		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 linkuse as main transcript	c.1090A>T	p.Met364Leu	missense_variant	10/23	1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.0524

AC:

7969

AN:

151972

Hom.:

404

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0458

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0335

Gnomad OTH

AF:

0.0597

GnomAD3 exomes

AF:

0.0791

AC:

19840

AN:

250962

Hom.:

1397

AF XY:

0.0772

AC XY:

10473

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.0480

Gnomad EAS exome

AF:

0.207

Gnomad SAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.0702

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0611

GnomAD4 exome

AF:

0.0497

AC:

72523

AN:

1460568

Hom.:

3471

Cov.:

AF XY:

0.0513

AC XY:

37301

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.0217

Gnomad4 AMR exome

AF:

0.150

Gnomad4 ASJ exome

AF:

0.0474

Gnomad4 EAS exome

AF:

0.237

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.0671

Gnomad4 NFE exome

AF:

0.0325

Gnomad4 OTH exome

AF:

0.0591

GnomAD4 genome

AF:

0.0525

AC:

7980

AN:

152090

Hom.:

405

Cov.:

AF XY:

0.0589

AC XY:

4381

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0233

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.0458

Gnomad4 EAS

AF:

0.229

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.0750

Gnomad4 NFE

AF:

0.0335

Gnomad4 OTH

AF:

0.0600

Alfa

AF:

0.0462

Hom.:

286

Bravo

AF:

0.0538

TwinsUK

AF:

0.0321

AC:

119

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.0357

AC:

307

ExAC

AF:

0.0743

AC:

9017

Asia WGS

AF:

0.186

AC:

645

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4J;C2675491:Amyotrophic lateral sclerosis type 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Amyotrophic lateral sclerosis type 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.23

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

MutationTaster

Benign

0.0000036

P;P

PrimateAI

Uncertain

0.78

PROVEAN

Benign

1.1

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.029

Vest4

0.26

MutPred

0.24

Loss of MoRF binding (P = 0.3574);

MPC

0.29

ClinPred

0.062

GERP RS

4.9

Varity_R

0.20

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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