Genetic Variant AIF1L:p.Arg31Trp (chr9-131096861-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031426.4(AIF1L):c.91C>T(p.Arg31Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000912 in 1,534,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

AIF1L
NM_031426.4 missense, splice_region

Scores

Splicing: ADA: 0.01892

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.223

Variant links:

Genes affected

AIF1L (HGNC:28904): (allograft inflammatory factor 1 like) Enables actin filament binding activity. Predicted to be involved in actin filament bundle assembly and ruffle assembly. Located in actin cytoskeleton and focal adhesion. Colocalizes with actin filament. Biomarker of breast cancer. [provided by Alliance of Genome Resources, Apr 2022]

AIF1L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23422945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIF1L	NM_031426.4 link	c.91C>T	p.Arg31Trp	missense_variant, splice_region_variant	Exon 2 of 6	ENST00000247291.8	NP_113614.1	Q9BQI0-1
AIF1L	NM_001185095.2 link	c.91C>T	p.Arg31Trp	missense_variant, splice_region_variant	Exon 2 of 7		NP_001172024.1	Q9BQI0-2
AIF1L	NM_001185096.2 link	c.91C>T	p.Arg31Trp	missense_variant, splice_region_variant	Exon 2 of 6		NP_001172025.1	Q9BQI0-4
AIF1L	NR_033701.2 link	n.212C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIF1L	ENST00000247291.8 link	c.91C>T	p.Arg31Trp	missense_variant, splice_region_variant	Exon 2 of 6	1	NM_031426.4	ENSP00000247291.3		Q9BQI0-1
AIF1L	ENST00000372302.5 link	c.91C>T	p.Arg31Trp	missense_variant, splice_region_variant	Exon 2 of 6	2		ENSP00000361376.1		Q9BQI0-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000940

AC:

AN:

1382484

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

682216

show subpopulations

Gnomad4 AFR exome

AF:

0.000101

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000559

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000106

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91C>T (p.R31W) alteration is located in exon 2 (coding exon 2) of the AIF1L gene. This alteration results from a C to T substitution at nucleotide position 91, causing the arginine (R) at amino acid position 31 to be replaced by a tryptophan (W). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.064

.;T;.;.;.

Eigen

Benign

0.015

Eigen_PC

Benign

-0.0090

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.60

T;T;T;T;T

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.1

L;L;L;L;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.94

N;D;D;D;D

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.20

MutPred

0.44

Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);

MVP

0.60

MPC

0.91

ClinPred

0.75

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.019

dbscSNV1_RF

Benign

0.20

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over