rs56378532

Variant names:

• chr6-109715071-T-C
• rs56378532
• NM_014845.6:c.67-7T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.67-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,501,586 control chromosomes in the GnomAD database, including 2,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (175 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2245 hom.)
• Consequence: FIG4 NM_014845.6 splice_region, intron
• Scores: Splicing: ADA: 0.0005026
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.413
• 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: Illumina, ClinGen
• Charcot-Marie-Tooth disease type 4J

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 6-109715071-T-C is Benign according to our data. Variant chr6-109715071-T-C is described in ClinVar as Benign. ClinVar VariationId is 137374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 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.67-7T>C		splice_region 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.67-7T>C		splice_region intron	N/A	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.67-7T>C		splice_region intron	N/A	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.67-7T>C		splice_region intron	N/A	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6471 AN: 152178 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0728

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0157

Gnomad SAS AF: 0.0863

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0590 AC: 14749 AN: 250030 AF XY: 0.0592

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0607

Gnomad EAS exome AF: 0.00849

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0538 AC: 72614 AN: 1349290 Hom.: 2245 Cov.: 21 AF XY: 0.0545 AC XY: 36943 AN XY: 677842

African (AFR) AF: 0.0155 AC: 488 AN: 31402

American (AMR) AF: 0.115 AC: 5126 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 1635 AN: 25356

East Asian (EAS) AF: 0.0198 AC: 773 AN: 39078

South Asian (SAS) AF: 0.0796 AC: 6674 AN: 83832

European-Finnish (FIN) AF: 0.0335 AC: 1775 AN: 52950

Middle Eastern (MID) AF: 0.0287 AC: 156 AN: 5430

European-Non Finnish (NFE) AF: 0.0527 AC: 53201 AN: 1010248

Other (OTH) AF: 0.0493 AC: 2786 AN: 56490

GnomAD4 genome AF: 0.0426 AC: 6486 AN: 152296 Hom.: 175 Cov.: 32 AF XY: 0.0421 AC XY: 3134 AN XY: 74466

African (AFR) AF: 0.0190 AC: 788 AN: 41568

American (AMR) AF: 0.0731 AC: 1118 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3472

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5196

South Asian (SAS) AF: 0.0861 AC: 415 AN: 4818

European-Finnish (FIN) AF: 0.0267 AC: 283 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0505 AC: 3436 AN: 68016

Other (OTH) AF: 0.0474 AC: 100 AN: 2108

Alfa AF: 0.0469 Hom.: 99

Bravo AF: 0.0458

Asia WGS AF: 0.0570 AC: 199 AN: 3474

EpiCase AF: 0.0526

EpiControl AF: 0.0517

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Amyotrophic lateral sclerosis type 11 (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.0
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: rs56378532; hg19: chr6-110036274; COSMIC: COSV57787997; COSMIC: COSV57787997;