dbSNP rs150821143: AIFM1:p.Pro548Pro (chrX-130130096-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004208.4(AIFM1):c.1644G>A(p.Pro548Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,209,955 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P548P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00024 ( 0 hom. 79 hem. )

Consequence

AIFM1
NM_004208.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.720

Publications

2 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:

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:

ENSG00000286650 (HGNC:):

ENSG00000286650 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant X-130130096-C-T is Benign according to our data. Variant chrX-130130096-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.72 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIFM1	NM_004208.4	MANE Select	c.1644G>A	p.Pro548Pro	synonymous	Exon 15 of 16	NP_004199.1	O95831-1
AIFM1	NM_145812.3		c.1632G>A	p.Pro544Pro	synonymous	Exon 15 of 16	NP_665811.1	O95831-3
AIFM1	NM_001130846.4		c.627G>A	p.Pro209Pro	synonymous	Exon 6 of 7	NP_001124318.2	E9PMA0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIFM1	ENST00000287295.8	TSL:1 MANE Select	c.1644G>A	p.Pro548Pro	synonymous	Exon 15 of 16	ENSP00000287295.3	O95831-1
AIFM1	ENST00000675092.1		c.1671G>A	p.Pro557Pro	synonymous	Exon 15 of 16	ENSP00000501772.1	A0A6Q8PFE1
AIFM1	ENST00000319908.8	TSL:1	c.1638G>A	p.Pro546Pro	synonymous	Exon 15 of 16	ENSP00000315122.4	A0A7I2PK44

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000301

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000981

AC:

AN:

183443

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000240

AC:

264

AN:

1098203

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

363559

show subpopulations

African (AFR)

AF:

0.0000757

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000292

AC:

246

AN:

842086

Other (OTH)

AF:

0.000347

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000188

AC:

AN:

111752

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33928

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

30732

American (AMR)

AF:

0.00

AC:

AN:

10506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3587

South Asian (SAS)

AF:

0.00

AC:

AN:

2674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.000301

AC:

AN:

53154

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000478

Hom.:

Bravo

AF:

0.000193

EpiCase

AF:

0.000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

AIFM1-related disorder (1)

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

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Severe X-linked mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.7

(source)

DANN

Benign

0.54

PhyloP100

-0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over