rs180917336

Variant names:

• chr18-12329239-C-T
• rs180917336
• NM_006796.3:c.*326G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006796.3(AFG3L2):​c.*326G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 702,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: AFG3L2 NM_006796.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000231 (127/550004) while in subpopulation AMR AF = 0.00245 (85/34692). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAdExome4. There are 60 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*326G>A		3_prime_UTR	Exon 17 of 17	NP_006787.2	Q9Y4W6
	TUBB6	NM_001303525.2		c.*56C>T		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.*326G>A		3_prime_UTR	Exon 17 of 17	ENSP00000269143.2	Q9Y4W6
	TUBB6	ENST00000591909.5	TSL:1	c.*56C>T		3_prime_UTR	Exon 4 of 4	ENSP00000465040.1	K7EJ64
	AFG3L2	ENST00000889396.1		c.*326G>A		3_prime_UTR	Exon 18 of 18	ENSP00000559455.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 127 AN: 550004 Hom.: 0 Cov.: 0 AF XY: 0.000201 AC XY: 60 AN XY: 297768

African (AFR) AF: 0.00 AC: 0 AN: 15798

American (AMR) AF: 0.00245 AC: 85 AN: 34692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20006

East Asian (EAS) AF: 0.00 AC: 0 AN: 32100

South Asian (SAS) AF: 0.00 AC: 0 AN: 62714

European-Finnish (FIN) AF: 0.0000298 AC: 1 AN: 33544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3698

European-Non Finnish (NFE) AF: 0.000120 AC: 38 AN: 316890

Other (OTH) AF: 0.0000982 AC: 3 AN: 30562

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74492

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spinocerebellar ataxia type 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.56
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs180917336; hg19: chr18-12329238;