6-109691426-TGCCGCCGCCATGCCCACG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014845.6(FIG4):c.1_18del(p.MetProThrAlaAlaAla1_?6) variant causes a start lost, 5 prime UTR change. The variant allele was found at a frequency of 0.00000282 in 1,420,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FIG4 NM_014845.6 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.54

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-109691426-TGCCGCCGCCATGCCCACG-T is Pathogenic according to our data. Variant chr6-109691426-TGCCGCCGCCATGCCCACG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1431306.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIG4	NM_014845.6	c.1_18del	p.MetProThrAlaAlaAla1_?6	start_lost, 5_prime_UTR_variant	1/23	ENST00000230124.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIG4	ENST00000230124.8	c.1_18del	p.MetProThrAlaAlaAla1_?6	start_lost, 5_prime_UTR_variant	1/23	1	NM_014845.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1420210 Hom.: 0 AF XY: 0.00000427 AC XY: 3 AN XY: 702760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000367

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 24, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FIG4 protein in which other variant(s) (p.Ile41Thr) have been determined to be pathogenic (PMID: 17572665, 18556664, 21705420, 23489662, 24878229; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with FIG4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the FIG4 mRNA. The next in-frame methionine is located at codon 78. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110012629;