rs10499054

Variant names:

• chr6-109785031-A-G
• rs10499054
• NM_014845.6:c.1948+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-109785031-A-G
• chr6-109785031-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.1948+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.598 in 1,518,784 control chromosomes in the GnomAD database, including 287,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21481 hom., cov: 32)
  • Exomes 𝑓: 0.61 (265699 hom.)
• Consequence: FIG4 NM_014845.6 splice_region, intron
• Scores: Splicing: ADA: 0.04755
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 4.54

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 6-109785031-A-G is Benign according to our data. Variant chr6-109785031-A-G is described in ClinVar as [Benign]. Clinvar id is 260447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109785031-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.1948+3A>G		splice_region_variant, intron_variant	Intron 17 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.1885+3A>G		splice_region_variant, intron_variant	Intron 17 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.1948+3A>G		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74492 AN: 151876 Hom.: 21490 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.520

GnomAD3 exomes AF: 0.528 AC: 132285 AN: 250486 Hom.: 38211 AF XY: 0.533 AC XY: 72215 AN XY: 135394

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.555

Gnomad EAS exome AF: 0.332

Gnomad SAS exome AF: 0.357

Gnomad FIN exome AF: 0.556

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.610 AC: 833467 AN: 1366790 Hom.: 265699 Cov.: 22 AF XY: 0.604 AC XY: 414332 AN XY: 685482

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.490 AC: 74484 AN: 151994 Hom.: 21481 Cov.: 32 AF XY: 0.480 AC XY: 35659 AN XY: 74292

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.327

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.516

Alfa AF: 0.623 Hom.: 52268

Bravo AF: 0.478

Asia WGS AF: 0.313 AC: 1089 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

-

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:2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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. -

Aug 10, 2021

Genome-Nilou Lab

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

- -

not provided Benign:1

Mar 03, 2015

GeneDx

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
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.048
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.020		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: rs10499054; hg19: chr6-110106234; COSMIC: COSV57789230; COSMIC: COSV57789230;