chr6-109691254-G-A

Variant names:

• chr6-109691254-G-A
• rs55873083
• ENST00000675726.1:c.-182G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000675726.1(FIG4):​c.-182G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 642,570 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (75 hom.)
• Consequence: FIG4 ENST00000675726.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.721
• Publications: 3 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=-0.82).
• BP6: Variant 6-109691254-G-A is Benign according to our data. Variant chr6-109691254-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 355024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1811/152280) while in subpopulation NFE AF = 0.0174 (1185/67994). AF 95% confidence interval is 0.0166. There are 14 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675726.1. 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
	AK9	NM_001145128.3	MANE Select	c.-119C>T		upstream_gene	N/A	NP_001138600.2	Q5TCS8-4
	FIG4	NM_014845.6	MANE Select	c.-182G>A		upstream_gene	N/A	NP_055660.1	Q92562
	AK9	NM_001329603.2		c.-795C>T		upstream_gene	N/A	NP_001316532.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	ENST00000675726.1		c.-182G>A		5_prime_UTR	Exon 1 of 22	ENSP00000502452.1	A0A6Q8PGY7
	FIG4	ENST00000675844.1		c.-166+340G>A		intron	N/A	ENSP00000502353.1	A0A6Q8PGP1
	FIG4	ENST00000675122.1		n.-182G>A		non_coding_transcript_exon	Exon 1 of 24	ENSP00000501810.1	A0A6Q8PFJ3

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1810 AN: 152162 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0141 AC: 6920 AN: 490290 Hom.: 75 Cov.: 5 AF XY: 0.0136 AC XY: 3518 AN XY: 259562

African (AFR) AF: 0.00363 AC: 51 AN: 14052

American (AMR) AF: 0.0121 AC: 324 AN: 26870

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 268 AN: 15688

East Asian (EAS) AF: 0.00 AC: 0 AN: 31350

South Asian (SAS) AF: 0.00417 AC: 221 AN: 53030

European-Finnish (FIN) AF: 0.0155 AC: 492 AN: 31724

Middle Eastern (MID) AF: 0.0117 AC: 43 AN: 3680

European-Non Finnish (NFE) AF: 0.0180 AC: 5151 AN: 286228

Other (OTH) AF: 0.0134 AC: 370 AN: 27668

GnomAD4 genome AF: 0.0119 AC: 1811 AN: 152280 Hom.: 14 Cov.: 32 AF XY: 0.0114 AC XY: 852 AN XY: 74460

African (AFR) AF: 0.00296 AC: 123 AN: 41568

American (AMR) AF: 0.0133 AC: 204 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1185 AN: 67994

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0155 Hom.: 4

Bravo AF: 0.0120

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.82
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		-0.72
PromoterAI		0.13	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55873083; hg19: chr6-110012457;