rs1127771

chr6-109825100-G-Achr6-109825100-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014845.6(FIG4):c.2559G>A(p.Ser853=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,611,466 control chromosomes in the GnomAD database, including 144,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11207 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133281 hom.)
• Consequence: FIG4 NM_014845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.65

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-109825100-G-A is Benign according to our data. Variant chr6-109825100-G-A is described in ClinVar as [Benign]. Clinvar id is 260449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109825100-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIG4	NM_014845.6	c.2559G>A	p.Ser853=	synonymous_variant	23/23	ENST00000230124.8
FIG4	XM_011536281.4	c.2496G>A	p.Ser832=	synonymous_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIG4	ENST00000230124.8	c.2559G>A	p.Ser853=	synonymous_variant	23/23	1	NM_014845.6	P4

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54508 AN: 151896 Hom.: 11209 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.401

GnomAD3 exomes AF: 0.439 AC: 110072 AN: 250872 Hom.: 25733 AF XY: 0.447 AC XY: 60563 AN XY: 135596

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.575

Gnomad SAS exome AF: 0.549

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.422 AC: 615174 AN: 1459452 Hom.: 133281 Cov.: 35 AF XY: 0.426 AC XY: 309595 AN XY: 726214

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.548

Gnomad4 FIN exome AF: 0.420

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.359 AC: 54514 AN: 152014 Hom.: 11207 Cov.: 32 AF XY: 0.366 AC XY: 27153 AN XY: 74280

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.489

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.404

Alfa AF: 0.410 Hom.: 12951

Bravo AF: 0.352

Asia WGS AF: 0.550 AC: 1909 AN: 3478

EpiCase AF: 0.432

EpiControl AF: 0.434

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Amyotrophic lateral sclerosis type 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Charcot-Marie-Tooth disease type 4J Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Yunis-Varon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Bilateral parasagittal parieto-occipital polymicrogyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.17
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1127771; hg19: chr6-110146303; COSMIC: COSV57786296; COSMIC: COSV57786296;