rs119485093

Variant names:

• chr16-81315156-C-A
• rs119485093
• NM_022041.4:c.43C>A
• GAN p.Arg15Ser

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• giant axonal neuropathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: -2.0288 (below the threshold of 3.09). GenCC associations: The gene is linked to giant axonal neuropathy 1.
• PP5: Variant 16-81315156-C-A is Pathogenic according to our data. Variant chr16-81315156-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5036.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	NM_022041.4	MANE Select	c.43C>A	p.Arg15Ser	missense	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.-482C>A		5_prime_UTR	Exon 1 of 10	NP_001364415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAN	ENST00000648994.2	MANE Select	c.43C>A	p.Arg15Ser	missense	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.43C>A	p.Arg15Ser	missense	Exon 1 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.43C>A	p.Arg15Ser	missense	Exon 1 of 10	ENSP00000551054.1

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

African (AFR) AF: 0.00 AC: 0 AN: 29520

American (AMR) AF: 0.00 AC: 0 AN: 36994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24680

East Asian (EAS) AF: 0.00 AC: 0 AN: 34038

South Asian (SAS) AF: 0.00 AC: 0 AN: 78654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083756

Other (OTH) AF: 0.00 AC: 0 AN: 57904

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	1	-	Giant axonal neuropathy 1 (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.41	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.96	D
Sift4G	Uncertain	0.019	D
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.64
gMVP		0.52
Mutation Taster		=18/82	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs119485093;

hg19: chr16-81348761;