rs2273752

Positions:

• chr6-109738307-C-A
• chr6-109738307-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.647-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,579,074 control chromosomes in the GnomAD database, including 113,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9275 hom., cov: 32)
  • Exomes 𝑓: 0.38 (104109 hom.)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.200

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-109738307-C-A is Benign according to our data. Variant chr6-109738307-C-A is described in ClinVar as [Benign]. Clinvar id is 260451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109738307-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIG4	NM_014845.6	c.647-18C>A		intron_variant		ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.584-18C>A		intron_variant			XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.647-18C>A		intron_variant		1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51244 AN: 151660 Hom.: 9271 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.362

GnomAD3 exomes AF: 0.391 AC: 97958 AN: 250508 Hom.: 19875 AF XY: 0.397 AC XY: 53733 AN XY: 135454

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.375

Gnomad SAS exome AF: 0.448

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.378 AC: 539988 AN: 1427296 Hom.: 104109 Cov.: 28 AF XY: 0.382 AC XY: 271824 AN XY: 711978

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.471

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.416

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.338 AC: 51273 AN: 151778 Hom.: 9275 Cov.: 32 AF XY: 0.342 AC XY: 25335 AN XY: 74174

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.363

Alfa AF: 0.365 Hom.: 2329

Bravo AF: 0.332

Asia WGS AF: 0.422 AC: 1465 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.79
BranchPoint Hunter		1.0

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

Other links and lift over

dbSNP: rs2273752; hg19: chr6-110059510; COSMIC: COSV57790518;