rs724160020

Variant names:

• chrX-130136086-G-A
• rs724160020
• NM_004208.4:c.1264C>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 14 publications found

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]

ENSG00000286650 (HGNC:):

RAB33A (HGNC:9773): (RAB33A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. It is GTP-binding protein and may be involved in vesicle transport. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 162479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM1	NM_004208.4	c.1264C>T	p.Arg422Trp	missense_variant	Exon 12 of 16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8	c.1264C>T	p.Arg422Trp	missense_variant	Exon 12 of 16	1	NM_004208.4	ENSP00000287295.3
AIFM1	ENST00000675092.1	c.1264C>T	p.Arg422Trp	missense_variant	Exon 12 of 16			ENSP00000501772.1

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

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842083

Other (OTH) AF: 0.00 AC: 0 AN: 46097

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

-

Deafness Gene Diagnosis, Xijing Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jul 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AIFM1-related disorder Pathogenic:1

Feb 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 18, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ear malformation Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
MutationAssessor	Uncertain	2.8	.;.;.;M
PhyloP100		1.7
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
Mutation Taster		=6/94	disease causing (ClinVar)

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