chr6-109691426-TGCCGCCGCCATGCCCACG-T

Variant names:

• chr6-109691426-TGCCGCCGCCATGCCCACG-T
• rs2128375200
• NM_014845.6:c.1_18delATGCCCACGGCCGCCGCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_014845.6(FIG4):​c.1_18delATGCCCACGGCCGCCGCC​(p.Met1_Ala6del) variant causes a start lost, conservative inframe deletion change. The variant allele was found at a frequency of 0.00000282 in 1,420,210 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FIG4 NM_014845.6 start_lost, conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.54
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PP5: Variant 6-109691426-TGCCGCCGCCATGCCCACG-T is Pathogenic according to our data. Variant chr6-109691426-TGCCGCCGCCATGCCCACG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1431306.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1_18delATGCCCACGGCCGCCGCC	p.Met1_Ala6del	start_lost conservative_inframe_deletion	Exon 1 of 23	NP_055660.1	Q92562
	AK9	NM_001145128.3	MANE Select	c.-309_-292delCGTGGGCATGGCGGCGGC		upstream_gene	N/A	NP_001138600.2	Q5TCS8-4
	AK9	NM_001329603.2		c.-985_-968delCGTGGGCATGGCGGCGGC		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.1_18delATGCCCACGGCCGCCGCC	p.Met1_Ala6del	start_lost conservative_inframe_deletion	Exon 1 of 23	ENSP00000230124.4	Q92562
	FIG4	ENST00000674884.1		c.1_18delATGCCCACGGCCGCCGCC	p.Met1_Ala6del	start_lost conservative_inframe_deletion	Exon 1 of 23	ENSP00000502668.1	A0A6Q8PHH5
	FIG4	ENST00000674744.1		c.1_18delATGCCCACGGCCGCCGCC	p.Met1_Ala6del	start_lost conservative_inframe_deletion	Exon 1 of 23	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1420210 Hom.: 0 AF XY: 0.00000427 AC XY: 3 AN XY: 702760

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32504

American (AMR) AF: 0.00 AC: 0 AN: 39024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 37266

South Asian (SAS) AF: 0.00 AC: 0 AN: 80918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090670

Other (OTH) AF: 0.00 AC: 0 AN: 58688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000281198), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Charcot-Marie-Tooth disease type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

Splicing

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

Other links and lift over

dbSNP: rs2128375200; hg19: chr6-110012629;