22-20974598-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386814.1(AIFM3):c.584C>T(p.Thr195Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIFM3 NM_001386814.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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]

ACMG classification

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=0.3606634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM3	NM_001386814.1	c.584C>T	p.Thr195Ile	missense_variant	7/21	ENST00000440238.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM3	ENST00000440238.4	c.584C>T	p.Thr195Ile	missense_variant	7/21	1	NM_001386814.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.584C>T (p.T195I) alteration is located in exon 7 (coding exon 6) of the AIFM3 gene. This alteration results from a C to T substitution at nucleotide position 584, causing the threonine (T) at amino acid position 195 to be replaced by an isoleucine (I). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;.;.;T
Eigen	Benign	0.073
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.55	N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.69	P;P;.;P;P
Vest4		0.42
MutPred		0.41		Loss of catalytic residue at T195 (P = 0.0031);Loss of catalytic residue at T195 (P = 0.0031);Loss of catalytic residue at T195 (P = 0.0031);.;Loss of catalytic residue at T195 (P = 0.0031);
MVP		0.90
MPC		0.63
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1923507271; hg19: chr22-21328887;