Genetic Variant AIFM3:p.Arg123Leu (chr22-20974075-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001386814.1(AIFM3):c.368G>T(p.Arg123Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R123H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AIFM3
NM_001386814.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.82

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2779405).

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.368G>T	p.Arg123Leu	missense	Exon 5 of 21	NP_001373743.1	Q96NN9-1
AIFM3	NM_144704.3		c.368G>T	p.Arg123Leu	missense	Exon 5 of 21	NP_653305.1	Q96NN9-1
AIFM3	NM_001146288.2		c.386G>T	p.Arg129Leu	missense	Exon 5 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.368G>T	p.Arg123Leu	missense	Exon 5 of 21	ENSP00000390798.2	Q96NN9-1
AIFM3	ENST00000399163.6	TSL:1	c.368G>T	p.Arg123Leu	missense	Exon 5 of 20	ENSP00000382116.2	Q96NN9-3
AIFM3	ENST00000399167.6	TSL:2	c.368G>T	p.Arg123Leu	missense	Exon 5 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242726

AF XY:

0.00000758

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457232

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5090

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111244

Other (OTH)

AF:

0.00

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.13

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.017

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

3.8

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.10

Sift

Benign

0.064

Sift4G

Benign

0.28

Polyphen

0.017

Vest4

0.53

MutPred

0.45

Loss of methylation at R123 (P = 0.0258)

MVP

0.65

MPC

0.62

ClinPred

0.89

GERP RS

3.7

Varity_R

0.24

gMVP

0.41

Mutation Taster

=81/19

polymorphism

(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