rs759581558

Positions:

chr16-81356957-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_022041.4(GAN):c.806G>A(p.Arg269Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,306 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:1

Conservation

PhyloP100: 9.86

Variant links:

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]

GAN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-81356956-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAN	NM_022041.4 linkuse as main transcript	c.806G>A	p.Arg269Gln	missense_variant	4/11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1 linkuse as main transcript	c.167G>A	p.Arg56Gln	missense_variant	3/10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
GAN	ENST00000648994.2 linkuse as main transcript	c.806G>A	p.Arg269Gln	missense_variant	4/11	NM_022041.4	ENSP00000497351	P1
GAN	ENST00000648349.2 linkuse as main transcript	c.*514G>A		3_prime_UTR_variant, NMD_transcript_variant	3/10		ENSP00000498114
GAN	ENST00000650388.1 linkuse as main transcript	c.*163G>A		3_prime_UTR_variant, NMD_transcript_variant	2/9		ENSP00000498081

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251444

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461190

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726962

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000779

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Pathogenic:1Uncertain:2Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital	Feb 14, 2024	This variant is detected in homozyous state in a patient with a clinical diagnosis of giant axonal neuropathy, with the typical associated fizzy hair. This variant is present at extremely low frequency in population database (gnomAD v4 0.0005%). It has been reported in two siblings in a homozygous state with giant axonal neuropathy (PMID: 12655563). In silico analysis predicts this variant to be damaging (REVEL 0.78). A different amino acid change at the same position, p.(Arg269Trp), was also reported in a compound heterozygous state in patients with GAN-related conditions (PMID: 23248352, 23890932, 32999401). -
Likely benign, flagged submission	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 26, 2023	The GAN c.806G>A (p.Arg269Gln) missense variant results in the substitution of arginine at amino acid position 269 with glutamine. This variant has been reported in a homozygous state in two siblings with giant axonal neuropathy from reportedly non-consanguineous parents from the same village (PMID: 12655563). A different amino acid change at the same position, c.805C>T (p.Arg269Trp), was also reported in a compound heterozygous state with a missense variant of unknown significance in an affected female with an atypical giant axonal neuropathy phenotype (PMID: 23248352). The c.806G>A variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000011 in the total population (version 2.1.1). Based on the available evidence, the c.806G>A (p.Arg269Gln) variant is classified as a variant of uncertain significance for giant axonal neuropathy. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.87

Loss of phosphorylation at S272 (P = 0.0632);Loss of phosphorylation at S272 (P = 0.0632);

MVP

0.92

MPC

0.42

ClinPred

0.89

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over