16-81315225-G-T

Variant names:

• chr16-81315225-G-T
• rs1252273429
• NM_022041.4:c.112G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001377486.1(GAN):​c.-413G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GAN NM_001377486.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.91
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377486.1. 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.112G>T	p.Gly38Trp	missense	Exon 1 of 11	NP_071324.1	A0A0S2Z4W2
	GAN	NM_001377486.1		c.-413G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001364415.1
	GAN	NM_001377486.1		c.-413G>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.112G>T	p.Gly38Trp	missense	Exon 1 of 11	ENSP00000497351.1	Q9H2C0
	GAN	ENST00000718305.1		c.112G>T	p.Gly38Trp	missense	Exon 1 of 11	ENSP00000520738.1	Q9H2C0
	GAN	ENST00000880995.1		c.112G>T	p.Gly38Trp	missense	Exon 1 of 10	ENSP00000551054.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711206

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.00 AC: 0 AN: 41614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36574

South Asian (SAS) AF: 0.00 AC: 0 AN: 82132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098896

Other (OTH) AF: 0.00 AC: 0 AN: 59052

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.95	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.79		Gain of catalytic residue at L36 (P = 0.0183)
MVP		0.85
MPC		0.61
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.76

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

Other links and lift over

dbSNP: rs1252273429; hg19: chr16-81348830; COSMIC: COSV101634027; COSMIC: COSV101634027;