NM_014845.6:c.447-6_447-3dupTTTT

Variant names:

• chr6-109732618-TTTG-TTTGT
• rs11377100
• NM_014845.6:c.447-3dupT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.447-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (46681 hom., cov: 0)
  • Exomes 𝑓: 0.50 (24987 hom.)
  • Failed GnomAD Quality Control
• Consequence: FIG4 NM_014845.6 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• 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: Illumina, ClinGen
• Charcot-Marie-Tooth disease type 4J

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis type 11

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Yunis-Varon syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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: tttgttttttttttttttAGgta. 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 6-109732618-TTTG-TTTGT is Benign according to our data. Variant chr6-109732621-G-GT is described in ClinVar as Benign. ClinVar VariationId is 694980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	NM_014845.6	MANE Select	c.447-3dupT		splice_acceptor intron	N/A	NP_055660.1	Q92562

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.447-16_447-15insT		intron	N/A	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.447-16_447-15insT		intron	N/A	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.447-16_447-15insT		intron	N/A	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.795 AC: 117100 AN: 147288 Hom.: 46661 Cov.: 0

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.780

GnomAD2 exomes AF: 0.557 AC: 91581 AN: 164298 AF XY: 0.554

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.541

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.536

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.504 AC: 430169 AN: 853140 Hom.: 24987 Cov.: 17 AF XY: 0.505 AC XY: 223209 AN XY: 442374

African (AFR) AF: 0.540 AC: 10719 AN: 19864

American (AMR) AF: 0.498 AC: 18460 AN: 37060

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 10175 AN: 20208

East Asian (EAS) AF: 0.509 AC: 16719 AN: 32832

South Asian (SAS) AF: 0.496 AC: 33087 AN: 66744

European-Finnish (FIN) AF: 0.523 AC: 18419 AN: 35222

Middle Eastern (MID) AF: 0.547 AC: 2293 AN: 4190

European-Non Finnish (NFE) AF: 0.503 AC: 300774 AN: 598224

Other (OTH) AF: 0.503 AC: 19523 AN: 38796

GnomAD4 genome AF: 0.795 AC: 117151 AN: 147336 Hom.: 46681 Cov.: 0 AF XY: 0.792 AC XY: 56665 AN XY: 71576

African (AFR) AF: 0.908 AC: 36607 AN: 40318

American (AMR) AF: 0.761 AC: 11244 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2667 AN: 3440

East Asian (EAS) AF: 0.692 AC: 3489 AN: 5044

South Asian (SAS) AF: 0.683 AC: 3197 AN: 4684

European-Finnish (FIN) AF: 0.759 AC: 6916 AN: 9108

Middle Eastern (MID) AF: 0.740 AC: 213 AN: 288

European-Non Finnish (NFE) AF: 0.758 AC: 50603 AN: 66754

Other (OTH) AF: 0.780 AC: 1579 AN: 2024

Alfa AF: 0.556 Hom.: 1380

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	1	Charcot-Marie-Tooth disease (2)
-	-	1	Amyotrophic lateral sclerosis type 11 (1)
-	-	1	Bilateral parasagittal parieto-occipital polymicrogyria (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4J (1)
-	-	1	not provided (1)
-	-	1	Yunis-Varon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.095
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11377100; hg19: chr6-110053821; COSMIC: COSV108013145;