22-20973825-C-G

Variant names:

• chr22-20973825-C-G
• rs375928890
• NM_001386814.1:c.313C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001386814.1(AIFM3):​c.313C>G​(p.Leu105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,579,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: AIFM3 NM_001386814.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03693056).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM3	NM_001386814.1	MANE Select	c.313C>G	p.Leu105Val	missense	Exon 4 of 21	NP_001373743.1	Q96NN9-1
	AIFM3	NM_144704.3		c.313C>G	p.Leu105Val	missense	Exon 4 of 21	NP_653305.1	Q96NN9-1
	AIFM3	NM_001146288.2		c.331C>G	p.Leu111Val	missense	Exon 4 of 20	NP_001139760.1	Q96NN9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIFM3	ENST00000440238.4	TSL:1 MANE Select	c.313C>G	p.Leu105Val	missense	Exon 4 of 21	ENSP00000390798.2	Q96NN9-1
	AIFM3	ENST00000399163.6	TSL:1	c.313C>G	p.Leu105Val	missense	Exon 4 of 20	ENSP00000382116.2	Q96NN9-3
	AIFM3	ENST00000399167.6	TSL:2	c.313C>G	p.Leu105Val	missense	Exon 4 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000274 AC: 54 AN: 196874 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000586

Gnomad NFE exome AF: 0.000409

Gnomad OTH exome AF: 0.000403

GnomAD4 exome AF: 0.000351 AC: 501 AN: 1427650 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 256 AN XY: 706718

African (AFR) AF: 0.0000608 AC: 2 AN: 32910

American (AMR) AF: 0.000100 AC: 4 AN: 40006

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 38288

South Asian (SAS) AF: 0.000458 AC: 37 AN: 80776

European-Finnish (FIN) AF: 0.0000586 AC: 3 AN: 51208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.000405 AC: 443 AN: 1094846

Other (OTH) AF: 0.000186 AC: 11 AN: 59062

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68010

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000209 AC: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.10	N
PhyloP100		1.3
PROVEAN	Benign	0.060	N
REVEL	Benign	0.046
Sift	Benign	0.32	T
Sift4G	Benign	0.47	T
Polyphen		0.0020	B
Vest4		0.32
MVP		0.34
MPC		0.35
ClinPred		0.013	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.27
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs375928890; hg19: chr22-21328114;