6-109743725-A-T

Variant names:

• chr6-109743725-A-T
• rs2295837
• NM_014845.6:c.1090A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014845.6(FIG4):​c.1090A>T​(p.Met364Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,612,658 control chromosomes in the GnomAD database, including 3,876 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (405 hom., cov: 32)
  • Exomes 𝑓: 0.050 (3471 hom.)
• Consequence: FIG4 NM_014845.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 8.93
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016498268).
• BP6: Variant 6-109743725-A-T is Benign according to our data. Variant chr6-109743725-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 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.1090A>T	p.Met364Leu	missense	Exon 10 of 23	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.1090A>T	p.Met364Leu	missense	Exon 10 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.1108A>T	p.Met370Leu	missense	Exon 10 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.1084A>T	p.Met362Leu	missense	Exon 10 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7969 AN: 151972 Hom.: 404 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0597

GnomAD2 exomes AF: 0.0791 AC: 19840 AN: 250962 AF XY: 0.0772

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0497 AC: 72523 AN: 1460568 Hom.: 3471 Cov.: 31 AF XY: 0.0513 AC XY: 37301 AN XY: 726640

African (AFR) AF: 0.0217 AC: 725 AN: 33406

American (AMR) AF: 0.150 AC: 6713 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1237 AN: 26086

East Asian (EAS) AF: 0.237 AC: 9391 AN: 39676

South Asian (SAS) AF: 0.125 AC: 10815 AN: 86228

European-Finnish (FIN) AF: 0.0671 AC: 3574 AN: 53302

Middle Eastern (MID) AF: 0.0677 AC: 390 AN: 5760

European-Non Finnish (NFE) AF: 0.0325 AC: 36114 AN: 1111168

Other (OTH) AF: 0.0591 AC: 3564 AN: 60300

GnomAD4 genome AF: 0.0525 AC: 7980 AN: 152090 Hom.: 405 Cov.: 32 AF XY: 0.0589 AC XY: 4381 AN XY: 74342

African (AFR) AF: 0.0233 AC: 968 AN: 41520

American (AMR) AF: 0.117 AC: 1777 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.229 AC: 1175 AN: 5132

South Asian (SAS) AF: 0.139 AC: 671 AN: 4814

European-Finnish (FIN) AF: 0.0750 AC: 795 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2279 AN: 67992

Other (OTH) AF: 0.0600 AC: 127 AN: 2116

Alfa AF: 0.0462 Hom.: 286

Bravo AF: 0.0538

TwinsUK AF: 0.0321 AC: 119

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.0357 AC: 307

ExAC AF: 0.0743 AC: 9017

Asia WGS AF: 0.186 AC: 645 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		8.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.029	B
Vest4		0.26
MutPred		0.24		Loss of MoRF binding (P = 0.3574)
MPC		0.29
ClinPred		0.062	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.64
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2295837; hg19: chr6-110064928; COSMIC: COSV57790546; COSMIC: COSV57790546;