22-20973855-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001386814.1(AIFM3):c.343C>T(p.Pro115Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AIFM3 NM_001386814.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIFM3	NM_001386814.1	c.343C>T	p.Pro115Ser	missense_variant	4/21	ENST00000440238.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIFM3	ENST00000440238.4	c.343C>T	p.Pro115Ser	missense_variant	4/21	1	NM_001386814.1	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.19e-7 AC: 1 AN: 1391158 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 684640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 24, 2023

The c.343C>T (p.P115S) alteration is located in exon 4 (coding exon 3) of the AIFM3 gene. This alteration results from a C to T substitution at nucleotide position 343, causing the proline (P) at amino acid position 115 to be replaced by a serine (S). 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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.;.;.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.75
MutPred		0.90		Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);.;Gain of MoRF binding (P = 0.0474);
MVP		0.76
MPC		1.1
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.44
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-21328144;