16-81315127-G-A

Variant names:

• chr16-81315127-G-A
• rs768368918
• NM_022041.4:c.14G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377486.1(GAN):​c.-511G>A 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 0.00000329 in 1,519,456 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GAN NM_001377486.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34550762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAN	NM_022041.4	c.14G>A	p.Ser5Asn	missense_variant	Exon 1 of 11	ENST00000648994.2	NP_071324.1
GAN	NM_001377486.1	c.-511G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		NP_001364415.1
GAN	NM_001377486.1	c.-511G>A		5_prime_UTR_variant	Exon 1 of 10		NP_001364415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAN	ENST00000648994.2	c.14G>A	p.Ser5Asn	missense_variant	Exon 1 of 11		NM_022041.4	ENSP00000497351.1
GAN	ENST00000648349.2	n.14G>A		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000498114.1
GAN	ENST00000650388.1	n.14G>A		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000498081.1
GAN	ENST00000674788.1	n.139G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1367296 Hom.: 0 Cov.: 32 AF XY: 0.00000296 AC XY: 2 AN XY: 675540

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: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74412

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Giant axonal neuropathy 1 Uncertain:1

Jul 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GAN-related conditions. This sequence change replaces serine with asparagine at codon 5 of the GAN protein (p.Ser5Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.59	.;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.95	D
Sift4G	Uncertain	0.022	D;.
Polyphen		0.089	B;B
Vest4		0.20
MVP		0.83
MPC		0.12
ClinPred		0.92	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.41

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: rs768368918; hg19: chr16-81348732;