NM_014845.6:c.67-8564G>A

Variant names:

• chr6-109706514-G-A
• rs3799845
• NM_014845.6:c.67-8564G>A

Variant summary

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

The NM_014845.6(FIG4):​c.67-8564G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,034 control chromosomes in the GnomAD database, including 9,282 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 0.34 (9282 hom., cov: 32)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.67-8564G>A		intron_variant	Intron 1 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.3+4792G>A		intron_variant	Intron 1 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.67-8564G>A		intron_variant	Intron 1 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51565 AN: 151916 Hom.: 9277 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.339 AC: 51599 AN: 152034 Hom.: 9282 Cov.: 32 AF XY: 0.343 AC XY: 25469 AN XY: 74298

African (AFR) AF: 0.199 AC: 8246 AN: 41450

American (AMR) AF: 0.406 AC: 6213 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1649 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1994 AN: 5146

South Asian (SAS) AF: 0.441 AC: 2125 AN: 4824

European-Finnish (FIN) AF: 0.411 AC: 4344 AN: 10558

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.381 AC: 25870 AN: 67984

Other (OTH) AF: 0.362 AC: 765 AN: 2112

Alfa AF: 0.206 Hom.: 485

Bravo AF: 0.334

Asia WGS AF: 0.414 AC: 1439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.42
PhyloP100		0.067
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: rs3799845; hg19: chr6-110027717;