6-109820488-G-C

Variant names:

• chr6-109820488-G-C
• rs4947022
• NM_014845.6:c.2547-4600G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014845.6(FIG4):​c.2547-4600G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,780 control chromosomes in the GnomAD database, including 13,967 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13967 hom., cov: 30)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.358
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• Charcot-Marie-Tooth disease type 4J

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
• Yunis-Varon syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• amyotrophic lateral sclerosis type 11

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral parasagittal parieto-occipital polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	NM_014845.6	MANE Select	c.2547-4600G>C		intron	N/A	NP_055660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.2547-4600G>C		intron	N/A	ENSP00000230124.4
	FIG4	ENST00000674884.1		c.2565-4600G>C		intron	N/A	ENSP00000502668.1
	FIG4	ENST00000674744.1		c.2541-4600G>C		intron	N/A	ENSP00000501661.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62322 AN: 151662 Hom.: 13960 Cov.: 30

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.411 AC: 62348 AN: 151780 Hom.: 13967 Cov.: 30 AF XY: 0.421 AC XY: 31196 AN XY: 74158

African (AFR) AF: 0.257 AC: 10651 AN: 41400

American (AMR) AF: 0.504 AC: 7680 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1707 AN: 3468

East Asian (EAS) AF: 0.813 AC: 4170 AN: 5130

South Asian (SAS) AF: 0.641 AC: 3084 AN: 4814

European-Finnish (FIN) AF: 0.472 AC: 4961 AN: 10510

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28633 AN: 67910

Other (OTH) AF: 0.448 AC: 946 AN: 2110

Alfa AF: 0.261 Hom.: 667

Bravo AF: 0.406

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.33
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4947022; hg19: chr6-110141691; COSMIC: COSV57786264;