Genetic Variant AIFM3:p.Arg24Gln (chr22-20973346-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386814.1(AIFM3):c.71G>A(p.Arg24Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000523 in 1,454,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

AIFM3
NM_001386814.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Publications

1 publications found

Variant links:

Genes affected

AIFM3 (HGNC:26398): (apoptosis inducing factor mitochondria associated 3) Predicted to enable several functions, including 2 iron, 2 sulfur cluster binding activity; flavin adenine dinucleotide binding activity; and metal ion binding activity. Involved in execution phase of apoptosis. Located in cytosol; endoplasmic reticulum; and mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

AIFM3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15380874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM3	NM_001386814.1 link	c.71G>A	p.Arg24Gln	missense_variant	Exon 3 of 21	ENST00000440238.4	NP_001373743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIFM3	ENST00000440238.4 link	c.71G>A	p.Arg24Gln	missense_variant	Exon 3 of 21	1	NM_001386814.1	ENSP00000390798.2		Q96NN9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000850

AC:

AN:

235166

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000523

AC:

AN:

1454216

Hom.:

Cov.:

AF XY:

0.0000498

AC XY:

AN XY:

722946

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33284

American (AMR)

AF:

0.00

AC:

AN:

43632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25878

East Asian (EAS)

AF:

0.00

AC:

AN:

39332

South Asian (SAS)

AF:

0.00

AC:

AN:

85074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000658

AC:

AN:

1108950

Other (OTH)

AF:

0.0000333

AC:

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.71G>A (p.R24Q) alteration is located in exon 3 (coding exon 2) of the AIFM3 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

T;.;.;.;.;T

Eigen

Benign

0.073

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.93

.;D;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;.;.;.;L

PhyloP100

4.5

PROVEAN

Benign

-0.44

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0080

D;D;D;T;D;D

Sift4G

Benign

0.20

T;T;D;T;T;T

Polyphen

0.93

P;P;.;.;D;P

Vest4

0.31

MutPred

0.14

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);

MVP

0.62

MPC

0.66

ClinPred

0.34

GERP RS

4.2

Varity_R

0.14

gMVP

0.28

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over