rs119485093

Positions:

• chr16-81315156-C-A

Variant summary

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

The NM_022041.4(GAN):​c.43C>A​(p.Arg15Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 4.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.43C>A	p.Arg15Ser	missense_variant	1/11	ENST00000648994.2
GAN	NM_001377486.1	c.-482C>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.43C>A	p.Arg15Ser	missense_variant	1/11		NM_022041.4	P1
GAN	ENST00000674788.1	n.168C>A		non_coding_transcript_exon_variant	1/3
GAN	ENST00000648349.2	c.43C>A	p.Arg15Ser	missense_variant, NMD_transcript_variant	1/10
GAN	ENST00000650388.1	c.43C>A	p.Arg15Ser	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400382 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693864

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.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.41	N;N
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.96	D
Sift4G	Uncertain	0.019	D;.
Polyphen		0.015	B;B
Vest4		0.74
MutPred		0.79		Gain of phosphorylation at R15 (P = 0.0267);Gain of phosphorylation at R15 (P = 0.0267);
MVP		0.80
MPC		0.13
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.64
gMVP		0.52

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: rs119485093; hg19: chr16-81348761;