chr18-12329456-T-G

Variant names:

• chr18-12329456-T-G
• rs114203162
• NM_006796.3:c.*109A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

TUBB6 Gene-Disease associations (from GenCC):

• facial palsy, congenital, with ptosis and velopharyngeal dysfunction

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006796.3. 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
	AFG3L2	NM_006796.3	MANE Select	c.*109A>C		3_prime_UTR	Exon 17 of 17	NP_006787.2	Q9Y4W6
	TUBB6	NM_001303525.2		c.*273T>G		3_prime_UTR	Exon 4 of 4	NP_001290454.1	K7EJ64

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFG3L2	ENST00000269143.8	TSL:1 MANE Select	c.*109A>C		3_prime_UTR	Exon 17 of 17	ENSP00000269143.2	Q9Y4W6
	TUBB6	ENST00000591909.5	TSL:1	c.*273T>G		3_prime_UTR	Exon 4 of 4	ENSP00000465040.1	K7EJ64
	AFG3L2	ENST00000889396.1		c.*109A>C		3_prime_UTR	Exon 18 of 18	ENSP00000559455.1

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

African (AFR) AF: 0.0315 AC: 781 AN: 24802

American (AMR) AF: 0.00158 AC: 68 AN: 42986

Ashkenazi Jewish (ASJ) AF: 0.0000858 AC: 2 AN: 23302

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37630

South Asian (SAS) AF: 0.000143 AC: 11 AN: 76722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52016

Middle Eastern (MID) AF: 0.00214 AC: 7 AN: 3264

European-Non Finnish (NFE) AF: 0.000138 AC: 99 AN: 718328

Other (OTH) AF: 0.00202 AC: 93 AN: 46004

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

African (AFR) AF: 0.0293 AC: 1219 AN: 41584

American (AMR) AF: 0.00261 AC: 40 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00496 Hom.: 9

Bravo AF: 0.00963

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Spinocerebellar ataxia type 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.1
DANN	Benign	0.77
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism

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: rs114203162; hg19: chr18-12329455;