NM_014845.6:c.-120C>T

Variant names:

• chr6-109691316-C-T
• rs75045314
• NM_014845.6:c.-120C>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.-120C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 797,918 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (52 hom.)
• Consequence: FIG4 NM_014845.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-109691316-C-T is Benign according to our data. Variant chr6-109691316-C-T is described in ClinVar as Benign. ClinVar VariationId is 355030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 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.-120C>T		5_prime_UTR	Exon 1 of 23	NP_055660.1	Q92562
	AK9	NM_001145128.3	MANE Select	c.-181G>A		upstream_gene	N/A	NP_001138600.2	Q5TCS8-4
	AK9	NM_001329603.2		c.-857G>A		upstream_gene	N/A	NP_001316532.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000230124.8	TSL:1 MANE Select	c.-120C>T		5_prime_UTR	Exon 1 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.-120C>T		5_prime_UTR	Exon 1 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.-120C>T		5_prime_UTR	Exon 1 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3161 AN: 151636 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00240 AC: 1552 AN: 646166 Hom.: 52 Cov.: 8 AF XY: 0.00192 AC XY: 658 AN XY: 343542

African (AFR) AF: 0.0717 AC: 1243 AN: 17340

American (AMR) AF: 0.00288 AC: 100 AN: 34662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20320

East Asian (EAS) AF: 0.00 AC: 0 AN: 32362

South Asian (SAS) AF: 0.000219 AC: 14 AN: 64004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44800

Middle Eastern (MID) AF: 0.00189 AC: 8 AN: 4240

European-Non Finnish (NFE) AF: 0.0000911 AC: 36 AN: 395006

Other (OTH) AF: 0.00452 AC: 151 AN: 33432

GnomAD4 genome AF: 0.0209 AC: 3168 AN: 151752 Hom.: 94 Cov.: 32 AF XY: 0.0201 AC XY: 1492 AN XY: 74168

African (AFR) AF: 0.0735 AC: 3042 AN: 41374

American (AMR) AF: 0.00563 AC: 86 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67882

Other (OTH) AF: 0.0128 AC: 27 AN: 2106

Alfa AF: 0.00942 Hom.: 15

Bravo AF: 0.0235

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.83
DANN	Benign	0.76
PhyloP100		-1.3
PromoterAI		-0.060	Neutral
Mutation Taster		=300/0	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: rs75045314; hg19: chr6-110012519;