dbSNP rs1252273429: GAN:p.Gly38Arg (chr16-81315225-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_022041.4(GAN):c.112G>A(p.Gly38Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,072 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.91

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 6 ACMG points.

PM1

In a domain BTB (size 69) in uniprot entity GAN_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_022041.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4 link	c.112G>A	p.Gly38Arg	missense_variant	Exon 1 of 11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 link	c.-413G>A		5_prime_UTR_variant	Exon 1 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	ENST00000648994.2 link	c.112G>A	p.Gly38Arg	missense_variant	Exon 1 of 11	NM_022041.4	ENSP00000497351.1	Q9H2C0
GAN	ENST00000648349.2 link	n.112G>A		non_coding_transcript_exon_variant	Exon 1 of 10		ENSP00000498114.1	A0A3B3ITY2
GAN	ENST00000650388.1 link	n.112G>A		non_coding_transcript_exon_variant	Exon 1 of 9		ENSP00000498081.1	A0A0S2Z5G5
GAN	ENST00000674788.1 link	n.237G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431072

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711206

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:

9.10e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Uncertain:1

Oct 15, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GAN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 38 of the GAN protein (p.Gly38Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.035

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.95

Sift4G

Benign

0.40

T;.

Polyphen

0.97

D;D

Vest4

0.36

MutPred

0.74

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.87

MPC

0.59

ClinPred

0.98

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.76

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