6-109691462-C-T

Variant names:

• chr6-109691462-C-T
• rs141040807
• NM_014845.6:c.27C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_014845.6(FIG4):​c.27C>T​(p.Ile9Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,586,892 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (40 hom.)
• Consequence: FIG4 NM_014845.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.59
• Publications: 0 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]

AK9 (HGNC:33814): (adenylate kinase 9) The protein encoded by this gene catalyzes the interconversion of nucleosides, possessing both nucleoside monophosphate and diphosphate kinase activities. The encoded protein uses these interconversions to maintain nucleoside homeostasis. [provided by RefSeq, Jul 2016]

AK9 Gene-Disease associations (from GenCC):

• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-109691462-C-T is Benign according to our data. Variant chr6-109691462-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 40 AR,Unknown,AD gene

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.27C>T	p.Ile9Ile	synonymous	Exon 1 of 23	NP_055660.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.27C>T	p.Ile9Ile	synonymous	Exon 1 of 23	ENSP00000230124.4
	FIG4	ENST00000674884.1		c.27C>T	p.Ile9Ile	synonymous	Exon 1 of 23	ENSP00000502668.1
	FIG4	ENST00000674744.1		c.27C>T	p.Ile9Ile	synonymous	Exon 1 of 23	ENSP00000501661.1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00477 AC: 968 AN: 202902 AF XY: 0.00492

Gnomad AFR exome AF: 0.000672

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00699

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00518 AC: 7425 AN: 1434564 Hom.: 40 Cov.: 31 AF XY: 0.00526 AC XY: 3742 AN XY: 710944

African (AFR) AF: 0.000576 AC: 19 AN: 32958

American (AMR) AF: 0.00126 AC: 52 AN: 41170

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 566 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 38324

South Asian (SAS) AF: 0.00314 AC: 258 AN: 82204

European-Finnish (FIN) AF: 0.00712 AC: 363 AN: 51004

Middle Eastern (MID) AF: 0.00262 AC: 15 AN: 5728

European-Non Finnish (NFE) AF: 0.00530 AC: 5824 AN: 1098306

Other (OTH) AF: 0.00553 AC: 328 AN: 59282

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74486

African (AFR) AF: 0.000890 AC: 37 AN: 41582

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00576 AC: 392 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00489 Hom.: 2

Bravo AF: 0.00349

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	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)
-	-	1	FIG4-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Yunis-Varon syndrome;C1970011:Charcot-Marie-Tooth disease type 4J;C2675491:Amyotrophic lateral sclerosis type 11;C4013648:Bilateral parasagittal parieto-occipital polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		1.6
PromoterAI		-0.039	Neutral
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs141040807; hg19: chr6-110012665;