NM_004208.4:c.1030C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004208.4(AIFM1):c.1030C>T(p.Leu344Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,209,667 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000051 ( 0 hom. 21 hem. )

Consequence

AIFM1
NM_004208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:1

Conservation

PhyloP100: 3.05

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: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]

RAB33A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047244847).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000717 (8/111507) while in subpopulation EAS AF= 0.00225 (8/3555). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM1	NM_004208.4 link	c.1030C>T	p.Leu344Phe	missense_variant	Exon 10 of 16	ENST00000287295.8	NP_004199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIFM1	ENST00000287295.8 link	c.1030C>T	p.Leu344Phe	missense_variant	Exon 10 of 16	1	NM_004208.4	ENSP00000287295.3		O95831-1
AIFM1	ENST00000675092.1 link	c.1030C>T	p.Leu344Phe	missense_variant	Exon 10 of 16			ENSP00000501772.1		A0A6Q8PFE1

Frequencies

GnomAD3 genomes

AF:

0.0000718

AC:

AN:

111457

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

33675

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00224

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

183387

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

67835

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00245

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1098160

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000717

AC:

AN:

111507

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

33735

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00225

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000189

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deafness, X-linked 5

Pathogenic:2

Aug 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Deafness Gene Diagnosis, Xijing Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:2

Sep 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as heterozygous in several unrelated Chinese females with bilateral auditory neuropathy in published literature, and in one female with unilateral auditory neuropathy, suggesting possible X-linked dominant inheritance (PMID: 34175691, 32684920); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in 37/14851 (0.2491%) alleles from individuals of East Asian background in large population cohorts (gnomAD); unknown if this represents a pathogenic founder variant or a common benign variant in this population; This variant is associated with the following publications: (PMID: 31832524, Chai_2021_Editorial, 34175691, 32684920, 25986071, 35578252) -

Apr 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AIFM1 c.1030C>T; p.Leu344Phe variant (rs184474885, ClinVar Variation ID: 162477) is reported in the literature in individuals affected with auditory neuropathy, including affected heterozygous female patients (Song 2021, Wang 2020, Zong 2015). Additionally, this variant was found in an individual affected with Charcot-Marie-Tooth disease-4 (Chen 2022), and in an infant with focal seizures (Ma 2019). This variant is found in the East Asian population with an allele frequency of 0.25% (37/14,851 alleles, including 20 hemizygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.279). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Chen J et al. Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations. BMC Neurol. 2022 May 16;22(1):180. PMID: 35578252. Ma X et al. Genetic diagnosis of neonatal-onset seizures. Genes Dis. 2019 Feb 8;6(4):441-447. PMID: 31832524. Song M et al. Clinical characteristics of patients with unilateral auditory neuropathy. Am J Otolaryngol. 2021 Sep-Oct;42(5):103143. PMID: 34175691. Wang H et al. High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population. Neural Plast. 2020 Jul 1;2020:5625768. PMID: 32684920. Zong L et al. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J Med Genet. 2015 Aug;52(8):523-31. PMID: 25986071. -

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

Benign:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.5

.;.;.;L

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Benign

0.28

Sift

Benign

0.15

T;T;T;D

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.083, 0.81, 0.85

.;B;P;P

Vest4

0.65

MVP

0.95

MPC

1.1

ClinPred

0.14

GERP RS

4.3

Varity_R

0.78

gMVP

0.95

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