NM_001386814.1:c.367C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001386814.1(AIFM3):​c.367C>T​(p.Arg123Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,609,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

AIFM3
NM_001386814.1 missense

Scores

2
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26423502).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AIFM3NM_001386814.1 linkc.367C>T p.Arg123Cys missense_variant Exon 5 of 21 ENST00000440238.4 NP_001373743.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AIFM3ENST00000440238.4 linkc.367C>T p.Arg123Cys missense_variant Exon 5 of 21 1 NM_001386814.1 ENSP00000390798.2 Q96NN9-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000372
AC:
9
AN:
242138
Hom.:
0
AF XY:
0.0000152
AC XY:
2
AN XY:
131532
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000883
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000554
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000457
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000302
AC:
44
AN:
1456902
Hom.:
0
Cov.:
34
AF XY:
0.0000248
AC XY:
18
AN XY:
724406
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.0000676
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000758
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 02, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.367C>T (p.R123C) alteration is located in exon 5 (coding exon 4) of the AIFM3 gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 to be replaced by a cysteine (C). 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
0.15
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.32
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.22
T;.;.;.;.;T
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.26
T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.3
L;L;.;.;.;L
PROVEAN
Uncertain
-2.6
D;D;D;N;D;D
REVEL
Benign
0.21
Sift
Benign
0.034
D;D;D;D;D;D
Sift4G
Uncertain
0.049
D;D;D;D;D;D
Polyphen
0.98
D;D;.;.;D;D
Vest4
0.52
MVP
0.73
MPC
1.1
ClinPred
0.42
T
GERP RS
4.8
Varity_R
0.16
gMVP
0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370362252; hg19: chr22-21328363; COSMIC: COSV100104801; COSMIC: COSV100104801; API