16-81315039-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022041.4(GAN):c.-75G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,212,674 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (160 hom., cov: 33)
  • Exomes 𝑓: 0.023 (352 hom.)
• Consequence: GAN NM_022041.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.56

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-81315039-G-C is Benign according to our data. Variant chr16-81315039-G-C is described in ClinVar as [Benign]. Clinvar id is 320646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.-75G>C		5_prime_UTR_variant	1/11	ENST00000648994.2
GAN	NM_001377486.1	c.-599G>C		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.-75G>C		5_prime_UTR_variant	1/11		NM_022041.4	P1
GAN	ENST00000674788.1	n.51G>C		non_coding_transcript_exon_variant	1/3
GAN	ENST00000648349.2	c.-75G>C		5_prime_UTR_variant, NMD_transcript_variant	1/10

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5706 AN: 149152 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.00569

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0509

Gnomad EAS AF: 0.000404

Gnomad SAS AF: 0.0389

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0319

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0309

GnomAD4 exome AF: 0.0226 AC: 24079 AN: 1063406 Hom.: 352 Cov.: 16 AF XY: 0.0232 AC XY: 12035 AN XY: 519332

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0530

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0410

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0276

GnomAD4 genome AF: 0.0382 AC: 5704 AN: 149268 Hom.: 160 Cov.: 33 AF XY: 0.0376 AC XY: 2736 AN XY: 72832

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0509

Gnomad4 EAS AF: 0.000405

Gnomad4 SAS AF: 0.0384

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0306

Alfa AF: 0.0178 Hom.: 7

Bravo AF: 0.0382

Asia WGS AF: 0.0160 AC: 56 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Giant axonal neuropathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	10
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs117642837; hg19: chr16-81348644;