NM_014845.6:c.1961T>C

Variant names:

Variant summary

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

The NM_014845.6(FIG4):c.1961T>C(p.Val654Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,610,604 control chromosomes in the GnomAD database, including 51,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 12744 hom., cov: 32)

Exomes 𝑓: 0.20 ( 38539 hom. )

Consequence

FIG4
NM_014845.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 3.51

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9537024E-6).

BP6

Variant 6-109786314-T-C is Benign according to our data. Variant chr6-109786314-T-C is described in ClinVar as [Benign]. Clinvar id is 137377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109786314-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6 link	c.1961T>C	p.Val654Ala	missense_variant	Exon 18 of 23	ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 link	c.1898T>C	p.Val633Ala	missense_variant	Exon 18 of 23		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 link	c.1961T>C	p.Val654Ala	missense_variant	Exon 18 of 23	1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51380

AN:

151966

Hom.:

12703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.689

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.278

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.416

Gnomad SAS

AF:

0.443

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.302

GnomAD3 exomes

AF:

0.269

AC:

67455

AN:

251048

Hom.:

12095

AF XY:

0.266

AC XY:

36138

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.695

Gnomad AMR exome

AF:

0.271

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.406

Gnomad SAS exome

AF:

0.445

Gnomad FIN exome

AF:

0.223

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.197

AC:

287471

AN:

1458520

Hom.:

38539

Cov.:

AF XY:

0.203

AC XY:

147061

AN XY:

725726

show subpopulations

Gnomad4 AFR exome

AF:

0.710

Gnomad4 AMR exome

AF:

0.270

Gnomad4 ASJ exome

AF:

0.248

Gnomad4 EAS exome

AF:

0.397

Gnomad4 SAS exome

AF:

0.441

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.147

Gnomad4 OTH exome

AF:

0.247

GnomAD4 genome

AF:

0.339

AC:

51488

AN:

152084

Hom.:

12744

Cov.:

AF XY:

0.343

AC XY:

25497

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.690

Gnomad4 AMR

AF:

0.278

Gnomad4 ASJ

AF:

0.240

Gnomad4 EAS

AF:

0.417

Gnomad4 SAS

AF:

0.442

Gnomad4 FIN

AF:

0.227

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.305

Alfa

AF:

0.189

Hom.:

9818

Bravo

AF:

0.351

TwinsUK

AF:

0.147

AC:

546

ALSPAC

AF:

0.141

AC:

542

ESP6500AA

AF:

0.668

AC:

2945

ESP6500EA

AF:

0.152

AC:

1304

ExAC

AF:

0.275

AC:

33396

Asia WGS

AF:

0.455

AC:

1578

AN:

3478

EpiCase

AF:

0.160

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 11

Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Yunis-Varon syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bilateral parasagittal parieto-occipital polymicrogyria

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.17

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.015

MetaRNN

Benign

0.0000020

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.28

PROVEAN

Benign

0.95

REVEL

Benign

0.068

Sift

Benign

0.83

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.024

MPC

0.37

ClinPred

0.0017

GERP RS

1.3

Varity_R

0.020

gMVP

0.21

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

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