6-31616403-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001623.5(AIF1):c.256C>A(p.Leu86Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,613,010 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: AIF1 NM_001623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

AIF1 (HGNC:352): (allograft inflammatory factor 1) This gene encodes a protein that binds actin and calcium. This gene is induced by cytokines and interferon and may promote macrophage activation and growth of vascular smooth muscle cells and T-lymphocytes. Polymorphisms in this gene may be associated with systemic sclerosis. Alternative splicing results in multiple transcript variants, but the full-length and coding nature of some of these variants is not certain. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029285938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIF1	NM_001623.5	c.256C>A	p.Leu86Ile	missense_variant	5/6	ENST00000376059.8
AIF1	NM_001318970.2	c.94C>A	p.Leu32Ile	missense_variant	5/6
AIF1	NM_032955.3	c.94C>A	p.Leu32Ile	missense_variant	2/3
AIF1	XM_005248870.5	c.454C>A	p.Leu152Ile	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIF1	ENST00000376059.8	c.256C>A	p.Leu86Ile	missense_variant	5/6	1	NM_001623.5	P1
AIF1	ENST00000337917.11	c.298C>A	p.Leu100Ile	missense_variant	5/6	1
AIF1	ENST00000376049.4	c.94C>A	p.Leu32Ile	missense_variant	2/3	1
AIF1	ENST00000466820.1	n.871C>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152086 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000629 AC: 155 AN: 246336 Hom.: 0 AF XY: 0.000566 AC XY: 76 AN XY: 134328

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000461

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000570

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000377 AC: 550 AN: 1460806 Hom.: 1 Cov.: 36 AF XY: 0.000365 AC XY: 265 AN XY: 726718

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152204 Hom.: 1 Cov.: 31 AF XY: 0.000901 AC XY: 67 AN XY: 74402

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000375 Hom.: 1

Bravo AF: 0.000752

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00232 AC: 7

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.000552 AC: 65

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00101

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 29, 2023

The c.292C>A (p.L98I) alteration is located in exon 3 (coding exon 1) of the AIF1 gene. This alteration results from a C to A substitution at nucleotide position 292, causing the leucine (L) at amino acid position 98 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	Benign	0.22
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.044	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.083	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.39
MVP		0.48
MPC		0.69
ClinPred		0.020	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs141116503; hg19: chr6-31584180; COSMIC: COSV99047784; COSMIC: COSV99047784;