6-109732621-GT-GTT

Position:

• chr6-109732621-GT-GTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.447-3dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (46681 hom., cov: 0)
  • Exomes 𝑓: 0.50 (24987 hom.)
  • Failed GnomAD Quality Control
• Consequence: FIG4 NM_014845.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -0.0950

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 -16 ACMG points.

• BP6: Variant 6-109732621-G-GT is Benign according to our data. Variant chr6-109732621-G-GT is described in ClinVar as [Benign]. Clinvar id is 694980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIG4	NM_014845.6	c.447-3dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.384-3dup		splice_polypyrimidine_tract_variant, intron_variant			XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.447-3dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014845.6	ENSP00000230124	P4

Frequencies

GnomAD3 genomes AF: 0.795 AC: 117100 AN: 147288 Hom.: 46661 Cov.: 0

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.780

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.504 AC: 430169 AN: 853140 Hom.: 24987 Cov.: 17 AF XY: 0.505 AC XY: 223209 AN XY: 442374

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.504

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.503

GnomAD4 genome AF: 0.795 AC: 117151 AN: 147336 Hom.: 46681 Cov.: 0 AF XY: 0.792 AC XY: 56665 AN XY: 71576

Gnomad4 AFR AF: 0.908

Gnomad4 AMR AF: 0.761

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.759

Gnomad4 NFE AF: 0.758

Gnomad4 OTH AF: 0.780

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -

Charcot-Marie-Tooth disease Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -

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

- -

Amyotrophic lateral sclerosis type 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Charcot-Marie-Tooth disease type 4J 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

Aug 27, 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

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: rs11377100; hg19: chr6-110053824;