rs119485088

chr16-81365432-G-Achr16-81365432-G-Cchr16-81365432-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_022041.4(GAN):c.1456G>A(p.Glu486Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.65

Genes affected

GAN (HGNC:4137): (gigaxonin) This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 16-81365432-G-A is Pathogenic according to our data. Variant chr16-81365432-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81365432-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.1456G>A	p.Glu486Lys	missense_variant	9/11	ENST00000648994.2
GAN	NM_001377486.1	c.817G>A	p.Glu273Lys	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.1456G>A	p.Glu486Lys	missense_variant	9/11		NM_022041.4	P1
GAN	ENST00000567335.1	n.14G>A		non_coding_transcript_exon_variant	1/2	3
GAN	ENST00000648349.2	c.*1164G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10
GAN	ENST00000650388.1	c.*813G>A		3_prime_UTR_variant, NMD_transcript_variant	7/9

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151636 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151636 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74044

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:3 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 29, 2023	For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5030). This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 11062483, 20949505). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs119485088, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 486 of the GAN protein (p.Glu486Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 03, 2022	ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, BP4 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2019

The p.E486K variant (also known as c.1456G>A), located in coding exon 9 of the GAN gene, results from a G to A substitution at nucleotide position 1456. The glutamic acid at codon 486 is replaced by lysine, an amino acid with similar properties. This variant was homozygous in a Tunisian family and compound heterozygous with a nonsense variant in a French family with giant axonal neuropathy (GAN) (Bomont P et al. Nat. Genet., 2000 Nov;26:370-4). Another affected individual was found to carry this alteration in trans with a microdeletion involving exons 3-11 of the GAN gene (Mahammad S et al. J. Clin. Invest., 2013 May;123:1964-75). This variant was not reported in the ExAC database, with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	0.050
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.078	T;.
Polyphen		0.72	P;P
Vest4		0.93
MutPred		0.73		Gain of ubiquitination at E486 (P = 0.0131);Gain of ubiquitination at E486 (P = 0.0131);
MVP		0.90
MPC		0.14
ClinPred		0.72	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs119485088; hg19: chr16-81399037; COSMIC: COSV73720785;