NM_014845.6:c.67-8338G>T

Variant names:

• chr6-109706740-G-T
• rs2025148
• NM_014845.6:c.67-8338G>T

Variant summary

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

The NM_014845.6(FIG4):​c.67-8338G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 151,950 control chromosomes in the GnomAD database, including 9,280 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 (9280 hom., cov: 32)
• Consequence: FIG4 NM_014845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.66
• Publications: 9 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=-1.01).
• 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.67-8338G>T		intron_variant	Intron 1 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.3+5018G>T		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.67-8338G>T		intron_variant	Intron 1 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51566 AN: 151832 Hom.: 9275 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.427

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: 0.340 AC: 51600 AN: 151950 Hom.: 9280 Cov.: 32 AF XY: 0.343 AC XY: 25477 AN XY: 74266

African (AFR) AF: 0.199 AC: 8259 AN: 41446

American (AMR) AF: 0.406 AC: 6204 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1650 AN: 3470

East Asian (EAS) AF: 0.388 AC: 2002 AN: 5160

South Asian (SAS) AF: 0.440 AC: 2121 AN: 4816

European-Finnish (FIN) AF: 0.413 AC: 4347 AN: 10530

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25856 AN: 67936

Other (OTH) AF: 0.362 AC: 766 AN: 2114

Alfa AF: 0.373 Hom.: 5611

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	-1.0
CADD	Benign	0.035
DANN	Benign	0.49
PhyloP100		-3.7
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: rs2025148; hg19: chr6-110027943;