rs61730896

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004208.4(AIFM1):c.103C>T(p.Pro35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,189,312 control chromosomes in the GnomAD database, including 6 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., 153 hem., cov: 24)

Exomes 𝑓: 0.00059 ( 3 hom. 169 hem. )

Consequence

AIFM1
NM_004208.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.47

Publications

5 publications found

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:

ENSG00000286650 (HGNC:):

ENSG00000286650 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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008270264).

BP6

Variant X-130165554-G-A is Benign according to our data. Variant chrX-130165554-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (521/112787) while in subpopulation AFR AF = 0.016 (498/31128). AF 95% confidence interval is 0.0148. There are 3 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM1	NM_004208.4 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 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.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 16	1	NM_004208.4	ENSP00000287295.3		O95831-1
AIFM1	ENST00000675092.1 link	c.103C>T	p.Pro35Ser	missense_variant	Exon 1 of 16			ENSP00000501772.1		A0A6Q8PFE1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

520

AN:

112737

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000364

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000563

Gnomad OTH

AF:

0.00458

GnomAD2 exomes

AF:

0.00136

AC:

192

AN:

141189

AF XY:

0.000932

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.000755

Gnomad ASJ exome

AF:

0.000149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000348

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.000593

AC:

638

AN:

1076525

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

169

AN XY:

351005

show subpopulations

African (AFR)

AF:

0.0194

AC:

502

AN:

25941

American (AMR)

AF:

0.00107

AC:

AN:

32584

Ashkenazi Jewish (ASJ)

AF:

0.0000528

AC:

AN:

18933

East Asian (EAS)

AF:

0.00

AC:

AN:

29067

South Asian (SAS)

AF:

0.0000389

AC:

AN:

51473

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38906

Middle Eastern (MID)

AF:

0.00219

AC:

AN:

4105

European-Non Finnish (NFE)

AF:

0.0000241

AC:

AN:

830302

Other (OTH)

AF:

0.00153

AC:

AN:

45214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00462

AC:

521

AN:

112787

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

153

AN XY:

34945

show subpopulations

African (AFR)

AF:

0.0160

AC:

498

AN:

31128

American (AMR)

AF:

0.00102

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.000366

AC:

AN:

2735

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6212

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000563

AC:

AN:

53290

Other (OTH)

AF:

0.00453

AC:

AN:

1546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000928

Hom.:

Bravo

AF:

0.00557

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00134

AC:

159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 23, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease X-linked recessive 4;C1845095:Deafness, X-linked 5;C1846148:Spondyloepimetaphyseal dysplasia, Bieganski type;C3151753:Severe X-linked mitochondrial encephalomyopathy

Benign:1

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Severe X-linked mitochondrial encephalomyopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Jan 29, 2025

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

Benign

0.071

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;.;.;T

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.48

T;T;.;T

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.1

M;M;M;M

PhyloP100

1.5

PrimateAI

Benign

0.45

PROVEAN

Benign

0.47

N;N;.;N

REVEL

Benign

0.022

Sift

Uncertain

0.012

D;T;.;T

Sift4G

Uncertain

0.040

D;T;T;T

Polyphen

0.31

B;B;.;B

Vest4

0.41

MVP

0.88

MPC

0.65

ClinPred

0.012

GERP RS

2.8

PromoterAI

0.096

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.096

gMVP

0.54

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over