22-20973436-G-A

Variant names:

• chr22-20973436-G-A
• rs771256400
• NM_001386814.1:c.161G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386814.1(AIFM3):​c.161G>A​(p.Arg54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AIFM3 NM_001386814.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0957205).

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.161G>A	p.Arg54His	missense	Exon 3 of 21	NP_001373743.1	Q96NN9-1
	AIFM3	NM_144704.3		c.161G>A	p.Arg54His	missense	Exon 3 of 21	NP_653305.1	Q96NN9-1
	AIFM3	NM_001146288.2		c.179G>A	p.Arg60His	missense	Exon 3 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.161G>A	p.Arg54His	missense	Exon 3 of 21	ENSP00000390798.2	Q96NN9-1
	AIFM3	ENST00000399163.6	TSL:1	c.161G>A	p.Arg54His	missense	Exon 3 of 20	ENSP00000382116.2	Q96NN9-3
	AIFM3	ENST00000399167.6	TSL:2	c.161G>A	p.Arg54His	missense	Exon 3 of 21	ENSP00000382120.2	Q96NN9-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248910 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460812 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52578

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N
PhyloP100		1.9
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.032
Sift	Benign	0.38	T
Sift4G	Benign	0.30	T
Polyphen		0.018	B
Vest4		0.17
MutPred		0.18		Loss of sheet (P = 0.0228)
MVP		0.57
MPC		0.43
ClinPred		0.17	T
GERP RS		3.8
Varity_R		0.068
gMVP		0.59
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771256400; hg19: chr22-21327725; COSMIC: COSV59004074; COSMIC: COSV59004074;