chr6-109691352-A-G

Variant names:

• chr6-109691352-A-G
• rs764845399
• NM_014845.6:c.-84A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014845.6(FIG4):​c.-84A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,100,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: FIG4 NM_014845.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.302
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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.-84A>G		5_prime_UTR	Exon 1 of 23	NP_055660.1	Q92562
	AK9	NM_001145128.3	MANE Select	c.-217T>C		upstream_gene	N/A	NP_001138600.2	Q5TCS8-4
	AK9	NM_001329603.2		c.-893T>C		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.-84A>G		5_prime_UTR	Exon 1 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.-84A>G		5_prime_UTR	Exon 1 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.-84A>G		5_prime_UTR	Exon 1 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 173 AN: 949022 Hom.: 0 Cov.: 13 AF XY: 0.000187 AC XY: 91 AN XY: 486066

African (AFR) AF: 0.0000864 AC: 2 AN: 23158

American (AMR) AF: 0.000199 AC: 7 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22326

East Asian (EAS) AF: 0.00 AC: 0 AN: 33832

South Asian (SAS) AF: 0.000199 AC: 14 AN: 70254

European-Finnish (FIN) AF: 0.000309 AC: 15 AN: 48466

Middle Eastern (MID) AF: 0.000208 AC: 1 AN: 4798

European-Non Finnish (NFE) AF: 0.000187 AC: 125 AN: 667904

Other (OTH) AF: 0.000209 AC: 9 AN: 43154

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74204

African (AFR) AF: 0.00 AC: 0 AN: 41342

American (AMR) AF: 0.000131 AC: 2 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000185

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 11 (1)
-	1	-	Charcot-Marie-Tooth disease type 4J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.44
PhyloP100		-0.30
PromoterAI		0.12	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: rs764845399; hg19: chr6-110012555;