Genetic Variant AIFM3:p.Arg125Trp (chr22-20974080-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386814.1(AIFM3):c.373C>T(p.Arg125Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,458,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AIFM3
NM_001386814.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.373C>T	p.Arg125Trp	missense	Exon 5 of 21	NP_001373743.1	Q96NN9-1
AIFM3	NM_144704.3		c.373C>T	p.Arg125Trp	missense	Exon 5 of 21	NP_653305.1	Q96NN9-1
AIFM3	NM_001146288.2		c.391C>T	p.Arg131Trp	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.373C>T	p.Arg125Trp	missense	Exon 5 of 21	ENSP00000390798.2	Q96NN9-1
AIFM3	ENST00000399163.6	TSL:1	c.373C>T	p.Arg125Trp	missense	Exon 5 of 20	ENSP00000382116.2	Q96NN9-3
AIFM3	ENST00000399167.6	TSL:2	c.373C>T	p.Arg125Trp	missense	Exon 5 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000820

AC:

AN:

244010

AF XY:

0.00000754

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:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1458064

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5160

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111426

Other (OTH)

AF:

0.00

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.2

PhyloP100

3.6

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.63

MutPred

0.65

Loss of methylation at R123 (P = 0.032)

MVP

0.77

MPC

1.1

ClinPred

1.0

GERP RS

3.8

Varity_R

0.69

gMVP

0.67

Mutation Taster

=70/30

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over