18-12329456-T-G

Position:

• chr18-12329456-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006796.3(AFG3L2):​c.*109A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,177,410 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: AFG3L2 NM_006796.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.922

Genes affected

AFG3L2 (HGNC:315): (AFG3 like matrix AAA peptidase subunit 2) This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders. [provided by RefSeq, Jul 2008]

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 18-12329456-T-G is Benign according to our data. Variant chr18-12329456-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 326100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00842 (1283/152356) while in subpopulation AFR AF= 0.0293 (1219/41584). AF 95% confidence interval is 0.0279. There are 21 homozygotes in gnomad4. There are 607 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.*109A>C		3_prime_UTR_variant	17/17	ENST00000269143.8	NP_006787.2
TUBB6	NM_001303525.2	c.*273T>G		3_prime_UTR_variant	4/4		NP_001290454.1
AFG3L2	XM_011525601.4	c.*109A>C		3_prime_UTR_variant	16/16		XP_011523903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8	c.*109A>C		3_prime_UTR_variant	17/17	1	NM_006796.3	ENSP00000269143	P1

Frequencies

GnomAD3 genomes AF: 0.00841 AC: 1280 AN: 152238 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00104 AC: 1062 AN: 1025054 Hom.: 14 Cov.: 14 AF XY: 0.000890 AC XY: 471 AN XY: 529152

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.0000858

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00842 AC: 1283 AN: 152356 Hom.: 21 Cov.: 33 AF XY: 0.00815 AC XY: 607 AN XY: 74504

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00707 Hom.: 3

Bravo AF: 0.00963

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	- -

Spinocerebellar ataxia type 28 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.1
DANN	Benign	0.77

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: rs114203162; hg19: chr18-12329455;