rs724160020

chrX-130136086-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004208.4(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 NM_004208.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.71

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 Pathogenic. Variant got 14 ACMG points.

• 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	UniProt
AIFM1	NM_004208.4	c.1264C>T	p.Arg422Trp	missense_variant	12/16	ENST00000287295.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM1	ENST00000287295.8	c.1264C>T	p.Arg422Trp	missense_variant	12/16	1	NM_004208.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363546

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.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deafness, X-linked 5 Pathogenic:2

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

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	Apr 06, 2023	Published functional studies suggest a damaging effect with impaired dimerization (Qiu et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25986071, 28967629, 31850270, 34416374, 32684920, 36751702) -

AIFM1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.059	T;.;.;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
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	D
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

Other links and lift over

dbSNP: rs724160020; hg19: chrX-129270061; COSMIC: COSV54855998; COSMIC: COSV54855998;