rs151344521

Positions:

• chr18-12337435-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006796.3(AFG3L2):​c.2081C>A​(p.Ala694Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFG3L2 NM_006796.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.56

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]

AFG3L2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 18-12337435-G-T is Pathogenic according to our data. Variant chr18-12337435-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5472.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-12337435-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFG3L2	NM_006796.3	c.2081C>A	p.Ala694Glu	missense_variant	16/17	ENST00000269143.8	NP_006787.2
AFG3L2	XM_011525601.4	c.1880C>A	p.Ala627Glu	missense_variant	15/16		XP_011523903.1
LOC107985154	XR_002958227.2	n.3291+533G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFG3L2	ENST00000269143.8	c.2081C>A	p.Ala694Glu	missense_variant	16/17	1	NM_006796.3	ENSP00000269143.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 28 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.82		Gain of disorder (P = 0.0316);
MVP		0.97
MPC		0.77
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.96

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: rs151344521; hg19: chr18-12337434;