16-81315127-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022041.4(GAN):c.14G>C(p.Ser5Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,367,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2816818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.14G>C	p.Ser5Thr	missense_variant	1/11	ENST00000648994.2
GAN	NM_001377486.1	c.-511G>C		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.14G>C	p.Ser5Thr	missense_variant	1/11		NM_022041.4	P1
GAN	ENST00000674788.1	n.139G>C		non_coding_transcript_exon_variant	1/3
GAN	ENST00000648349.2	c.14G>C	p.Ser5Thr	missense_variant, NMD_transcript_variant	1/10
GAN	ENST00000650388.1	c.14G>C	p.Ser5Thr	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000749 AC: 1 AN: 133498 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000457

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367296 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 675540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000301

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: 0.0000177

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Giant axonal neuropathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2020

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 (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. This variant has not been reported in the literature in individuals with GAN-related conditions. 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 sequence change replaces serine with threonine at codon 5 of the GAN protein (p.Ser5Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.95	D
PrimateAI	Pathogenic	0.94	D
Sift4G	Benign	0.28	T;.
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.21		Loss of glycosylation at S5 (P = 0.0249);Loss of glycosylation at S5 (P = 0.0249);
MVP		0.79
MPC		0.11
ClinPred		0.79	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.39

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: rs768368918; hg19: chr16-81348732;