rs724160020

Positions:

chrX-130136086-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000287295.8(AIFM1):c.1264C>T(p.Arg422Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,190 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

AIFM1
ENST00000287295.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.71

Variant links:

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]

AIFM1 links:

RAB33A (HGNC:):

RAB33A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a strand (size 2) in uniprot entity AIFM1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000287295.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-130136085-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

PP5

Variant X-130136086-G-A is Pathogenic according to our data. Variant chrX-130136086-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130136086-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIFM1	NM_004208.4 linkuse as main transcript	c.1264C>T	p.Arg422Trp	missense_variant	12/16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8 linkuse as main transcript	c.1264C>T	p.Arg422Trp	missense_variant	12/16	1	NM_004208.4	ENSP00000287295		O95831-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deafness, X-linked 5

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Deafness Gene Diagnosis, Xijing Hospital	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2015	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	Published functional studies suggest this variant is associated with impaired dimerization (PMID: 36751702); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25986071, 28967629, 34416374, 32684920, 38374194, 37405018, 36751702, 31850270) -

AIFM1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The AIFM1 c.1264C>T variant is predicted to result in the amino acid substitution p.Arg422Trp. This variant has been reported in male individuals with X-linked auditory neuropathy spectrum disorder (ANSD) and/or hearing loss (Zong et al. 2015. PubMed ID: 25986071; Bazazzadegan et al. 2019. PubMed ID: 31850270; Wang et al. 2020. PubMed ID: 32684920; Guan et al. 2021. PubMed ID: 34416374). In one of those families, this variant has been observed to segregate with ANSD, with female carriers not reporting any signs of ANSD or peripheral sensory neuropathy (Zong et al. 2015. PubMed ID: 25986071). This variant has not been reported in a large population database, indicating this variant is rare. A different substitution affecting the same amino acid (p.Arg422Gln) has also been documented in association with ANSD (Zong et al. 2015. PubMed ID: 25986071). This variant is interpreted as likely pathogenic. -

Severe X-linked mitochondrial encephalomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 18, 2023

- -

Ear malformation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in AIFM1. Other variant(s) that disrupt this residue have been observed in individuals with AIFM1-related conditions (PMID: 25986071), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIFM1 protein function. This variant has been observed in individual(s) with clinical features of AIFM1-related conditions (PMID: 25986071, 31850270). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162479). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 422 of the AIFM1 protein (p.Arg422Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.059

T;.;.;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.8

.;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.041

D;D;D;D

Sift4G

Benign

0.078

T;T;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.90

MutPred

0.62

.;.;.;Loss of methylation at R422 (P = 0.018);

MVP

0.88

MPC

1.7

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over