rs773384073

Variant names:

• chr16-81315130-C-T
• rs773384073
• NM_022041.4:c.17C>T
• GAN p.Ala6Val

Your query was ambiguous. Multiple possible variants found:

• chr16-81315130-C-T
• chr16-81315130-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022041.4(GAN):​c.17C>T​(p.Ala6Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,521,452 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 (★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12567788).

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.17C>T	p.Ala6Val	missense	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.-508C>T		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.17C>T	p.Ala6Val	missense	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000221 AC: 3 AN: 135692 AF XY: 0.0000134

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000291

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1369480 Hom.: 0 Cov.: 32 AF XY: 0.0000148 AC XY: 10 AN XY: 676770

African (AFR) AF: 0.0000356 AC: 1 AN: 28090

American (AMR) AF: 0.00 AC: 0 AN: 33448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24018

East Asian (EAS) AF: 0.0000320 AC: 1 AN: 31228

South Asian (SAS) AF: 0.00 AC: 0 AN: 76176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4584

European-Non Finnish (NFE) AF: 0.0000131 AC: 14 AN: 1067178

Other (OTH) AF: 0.00 AC: 0 AN: 56474

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151972 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.58	N
PhyloP100		4.3
PrimateAI	Pathogenic	0.95	D
Sift4G	Benign	0.95	T
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.28
gMVP		0.22
Mutation Taster		=85/15	polymorphism

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: rs773384073;

hg19: chr16-81348735;