16-81365420-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022041.4(GAN):c.1444G>T(p.Ala482Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A482V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07957804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.1444G>T	p.Ala482Ser	missense_variant	9/11	ENST00000648994.2
GAN	NM_001377486.1	c.805G>T	p.Ala269Ser	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.1444G>T	p.Ala482Ser	missense_variant	9/11		NM_022041.4	P1
GAN	ENST00000567335.1	n.2G>T		non_coding_transcript_exon_variant	1/2	3
GAN	ENST00000648349.2	c.*1152G>T		3_prime_UTR_variant, NMD_transcript_variant	8/10
GAN	ENST00000650388.1	c.*801G>T		3_prime_UTR_variant, NMD_transcript_variant	7/9

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Benign	0.37
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.59	T;.
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.36		Gain of phosphorylation at A482 (P = 0.0263);Gain of phosphorylation at A482 (P = 0.0263);
MVP		0.63
MPC		0.11
ClinPred		0.17	T
GERP RS		4.5
Varity_R		0.060
gMVP		0.16

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: rs369693274; hg19: chr16-81399025;