16-81354535-G-T

Position:

• chr16-81354535-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_022041.4(GAN):​c.413G>T​(p.Arg138Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain BACK (size 102) in uniprot entity GAN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_022041.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-81354535-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5035.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 16-81354535-G-T is Pathogenic according to our data. Variant chr16-81354535-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245992.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.413G>T	p.Arg138Leu	missense_variant	3/11	ENST00000648994.2
GAN	NM_001377486.1	c.-227G>T		5_prime_UTR_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.413G>T	p.Arg138Leu	missense_variant	3/11		NM_022041.4	P1
GAN	ENST00000674788.1	n.538G>T		non_coding_transcript_exon_variant	3/3
GAN	ENST00000648349.2	c.*121G>T		3_prime_UTR_variant, NMD_transcript_variant	2/10
GAN	ENST00000650388.1	c.168-2250G>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2015

A novel R138L variant that is likely pathogenic has also been identified in the GAN gene. The R138L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different amino acid substitution at the same position (R138H) has been previously reported as a homozygous variant in a family with mild CMT (Bomont et al., 2000; Bomont et al., 2003). The R138L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R138L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.82	P;P
Vest4		0.91
MutPred		0.87		Loss of catalytic residue at R138 (P = 0.0365);Loss of catalytic residue at R138 (P = 0.0365);
MVP		0.91
MPC		0.26
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs119485092; hg19: chr16-81388140;