Genetic Variant AIFM3:p.Pro110Gln (chr22-20973841-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001386814.1(AIFM3):c.329C>A(p.Pro110Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,403,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P110L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

AIFM3
NM_001386814.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.54

Publications

0 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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386814.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIFM3	NM_001386814.1	MANE Select	c.329C>A	p.Pro110Gln	missense	Exon 4 of 21	NP_001373743.1	Q96NN9-1
AIFM3	NM_144704.3		c.329C>A	p.Pro110Gln	missense	Exon 4 of 21	NP_653305.1	Q96NN9-1
AIFM3	NM_001146288.2		c.347C>A	p.Pro116Gln	missense	Exon 4 of 20	NP_001139760.1	Q96NN9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIFM3	ENST00000440238.4	TSL:1 MANE Select	c.329C>A	p.Pro110Gln	missense	Exon 4 of 21	ENSP00000390798.2	Q96NN9-1
AIFM3	ENST00000399163.6	TSL:1	c.329C>A	p.Pro110Gln	missense	Exon 4 of 20	ENSP00000382116.2	Q96NN9-3
AIFM3	ENST00000399167.6	TSL:2	c.329C>A	p.Pro110Gln	missense	Exon 4 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403416

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691956

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32322

American (AMR)

AF:

0.00

AC:

AN:

37084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24138

East Asian (EAS)

AF:

0.00

AC:

AN:

37282

South Asian (SAS)

AF:

0.00

AC:

AN:

78158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5232

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081058

Other (OTH)

AF:

0.00

AC:

AN:

58026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.024

MutationAssessor

Pathogenic

4.0

PhyloP100

5.5

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.47

Sift

Benign

0.050

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.85

MutPred

0.75

Loss of sheet (P = 0.0817)

MVP

0.89

MPC

1.1

ClinPred

1.0

GERP RS

4.8

Varity_R

0.20

gMVP

0.79

Mutation Taster

=31/69

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over