rs776278563

Variant names:

• chr22-20973841-C-T
• rs776278563
• NM_001386814.1:c.329C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-20973841-C-T
• chr22-20973841-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001386814.1(AIFM3):​c.329C>T​(p.Pro110Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000128 in 1,403,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000013 (0 hom.)
• Consequence: AIFM3 NM_001386814.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

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.329C>T	p.Pro110Leu	missense	Exon 4 of 21	NP_001373743.1	Q96NN9-1
	AIFM3	NM_144704.3		c.329C>T	p.Pro110Leu	missense	Exon 4 of 21	NP_653305.1	Q96NN9-1
	AIFM3	NM_001146288.2		c.347C>T	p.Pro116Leu	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.329C>T	p.Pro110Leu	missense	Exon 4 of 21	ENSP00000390798.2	Q96NN9-1
	AIFM3	ENST00000399163.6	TSL:1	c.329C>T	p.Pro110Leu	missense	Exon 4 of 20	ENSP00000382116.2	Q96NN9-3
	AIFM3	ENST00000399167.6	TSL:2	c.329C>T	p.Pro110Leu	missense	Exon 4 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000175 AC: 3 AN: 171298 AF XY: 0.0000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 18 AN: 1403416 Hom.: 0 Cov.: 33 AF XY: 0.0000159 AC XY: 11 AN XY: 691956

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.0000270 AC: 1 AN: 37084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24138

East Asian (EAS) AF: 0.00 AC: 0 AN: 37282

South Asian (SAS) AF: 0.0000256 AC: 2 AN: 78158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5232

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1081058

Other (OTH) AF: 0.00 AC: 0 AN: 58026

GnomAD4 genome Cov.: 33

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000253 AC: 3

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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.5
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.46
Sift	Benign	0.045	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.76		Gain of catalytic residue at P110 (P = 0.0387)
MVP		0.85
MPC		0.98
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.81
Mutation Taster		=40/60	disease causing

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: rs776278563; hg19: chr22-21328130; COSMIC: COSV104647576; COSMIC: COSV104647576;