Variant 16-81315123-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022041.4(GAN):c.10G>A(p.Gly4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GAN
NM_022041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.974

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19460857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4 link	c.10G>A	p.Gly4Ser	missense_variant	Exon 1 of 11	ENST00000648994.2	NP_071324.1	Q9H2C0A0A0S2Z4W2B3KTC3
GAN	NM_001377486.1 link	c.-515G>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.10G>A	p.Gly4Ser	missense_variant	Exon 1 of 11	NM_022041.4	ENSP00000497351.1	Q9H2C0
GAN	ENST00000648349.2 link	n.10G>A		non_coding_transcript_exon_variant	Exon 1 of 10		ENSP00000498114.1	A0A3B3ITY2
GAN	ENST00000650388.1 link	n.10G>A		non_coding_transcript_exon_variant	Exon 1 of 9		ENSP00000498081.1	A0A0S2Z5G5
GAN	ENST00000674788.1 link	n.135G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1362830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673024

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Giant axonal neuropathy 1

Uncertain:1

Feb 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with serine at codon 4 of the GAN protein (p.Gly4Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with GAN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.74

.;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.59

N;N

PrimateAI

Pathogenic

0.91

Sift4G

Benign

0.16

T;.

Polyphen

0.0050

B;B

Vest4

0.056

MutPred

0.12

Gain of phosphorylation at G4 (P = 0.0097);Gain of phosphorylation at G4 (P = 0.0097);

MVP

0.61

MPC

0.12

ClinPred

0.99

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.22

gMVP

0.38

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over