rs202219398

Positions:

• chrX-130133373-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_004208.4(AIFM1):​c.1388G>T​(p.Arg463Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,209,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00024 (0 hom. 70 hem.)
• Consequence: AIFM1 NM_004208.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:2
• Conservation: PhyloP100: 7.56

Genes affected

AIFM1 (HGNC:8768): (apoptosis inducing factor mitochondria associated 1) This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells, and it is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the translocation of this protein to the nucleus where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Mutations in this gene cause combined oxidative phosphorylation deficiency 6 (COXPD6), a severe mitochondrial encephalomyopathy, as well as Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4), a disorder resulting in neuropathy, and axonal and motor-sensory defects with deafness and cognitive disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 10. [provided by RefSeq, Aug 2015]

RAB33A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004208.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM1	NM_004208.4	c.1388G>T	p.Arg463Ile	missense_variant	13/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.1388G>T	p.Arg463Ile	missense_variant	13/16	1	NM_004208.4

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 12 AN: 110912 Hom.: 0 Cov.: 21 AF XY: 0.0000906 AC XY: 3 AN XY: 33098

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.000679

GnomAD3 exomes AF: 0.000185 AC: 34 AN: 183468 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000238 AC: 261 AN: 1098110 Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 70 AN XY: 363466

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000716

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000108 AC: 12 AN: 110912 Hom.: 0 Cov.: 21 AF XY: 0.0000906 AC XY: 3 AN XY: 33098

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000340

Gnomad4 NFE AF: 0.000170

Gnomad4 OTH AF: 0.000679

Alfa AF: 0.000201 Hom.: 6

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Mar 12, 2021

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Charcot-Marie-Tooth disease X-linked recessive 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Aug 18, 2015

Likely pathogenic based on conservation and prediction scores (Phylop, Polyphen, SIFT, MutationTaster) and consistent with neuropathy of patient. Patient also had Sotos syndrome with de novo frameshift insertion in NSD1 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2021

This variant is associated with the following publications: (PMID: 26257172, 32376792) -

Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.9	D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.93, 0.75, 0.33	.;P;P;B
Vest4		0.95
MVP		0.97
MPC		1.4
ClinPred		0.50	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202219398; hg19: chrX-129267348;