NM_014845.6:c.447-4_447-3dupTT

Variant names:

• chr6-109732621-G-GTT
• rs11377100
• NM_014845.6:c.447-4_447-3dupTT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_014845.6(FIG4):​c.447-4_447-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (17 hom., cov: 0)
  • Exomes 𝑓: 0.11 (5 hom.)
• Consequence: FIG4 NM_014845.6 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0950
• Publications: 4 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 -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018722467 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttgtttttttttttttttAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 6-109732621-G-GTT is Benign according to our data. Variant chr6-109732621-G-GTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 917084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00964 (1420/147268) while in subpopulation AFR AF = 0.0283 (1141/40298). AF 95% confidence interval is 0.0269. There are 17 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.447-4_447-3dupTT		splice_acceptor_variant, intron_variant	Intron 4 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.384-4_384-3dupTT		splice_acceptor_variant, intron_variant	Intron 4 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.447-16_447-15insTT		intron_variant	Intron 4 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1410 AN: 147222 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00637

Gnomad ASJ AF: 0.00262

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00551

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00697

GnomAD2 exomes AF: 0.0973 AC: 15986 AN: 164298 AF XY: 0.0991

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.0804

Gnomad FIN exome AF: 0.0729

Gnomad NFE exome AF: 0.0874

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.114 AC: 91472 AN: 800370 Hom.: 5 Cov.: 17 AF XY: 0.113 AC XY: 46895 AN XY: 413228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.213 AC: 3755 AN: 17652

American (AMR) AF: 0.101 AC: 3571 AN: 35282

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 2371 AN: 18390

East Asian (EAS) AF: 0.109 AC: 3281 AN: 30034

South Asian (SAS) AF: 0.106 AC: 6649 AN: 62846

European-Finnish (FIN) AF: 0.119 AC: 3782 AN: 31894

Middle Eastern (MID) AF: 0.0784 AC: 312 AN: 3982

European-Non Finnish (NFE) AF: 0.112 AC: 63397 AN: 564364

Other (OTH) AF: 0.121 AC: 4354 AN: 35926

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00964 AC: 1420 AN: 147268 Hom.: 17 Cov.: 0 AF XY: 0.00960 AC XY: 687 AN XY: 71538

African (AFR) AF: 0.0283 AC: 1141 AN: 40298

American (AMR) AF: 0.00636 AC: 94 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.00262 AC: 9 AN: 3438

East Asian (EAS) AF: 0.00158 AC: 8 AN: 5050

South Asian (SAS) AF: 0.00107 AC: 5 AN: 4688

European-Finnish (FIN) AF: 0.00551 AC: 50 AN: 9078

Middle Eastern (MID) AF: 0.0174 AC: 5 AN: 288

European-Non Finnish (NFE) AF: 0.00141 AC: 94 AN: 66728

Other (OTH) AF: 0.00692 AC: 14 AN: 2024

Alfa AF: 0.0986 Hom.: 1380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs11377100; hg19: chr6-110053824; COSMIC: COSV108013375;