Genetic Variant AIFM2:p.His271Pro (chr10-70115078-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032797.6(AIFM2):c.812A>C(p.His271Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AIFM2
NM_032797.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Variant links:

Genes affected

AIFM2 (HGNC:21411): (apoptosis inducing factor mitochondria associated 2) This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells. [provided by RefSeq, Nov 2010]

AIFM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIFM2	NM_032797.6 link	c.812A>C	p.His271Pro	missense_variant	Exon 8 of 9	ENST00000307864.3	NP_116186.1	Q9BRQ8-1
AIFM2	NM_001198696.2 link	c.812A>C	p.His271Pro	missense_variant	Exon 8 of 9		NP_001185625.1	Q9BRQ8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AIFM2	ENST00000307864.3 link	c.812A>C	p.His271Pro	missense_variant	Exon 8 of 9	1	NM_032797.6	ENSP00000312370.1	Q9BRQ8-1
AIFM2	ENST00000373248.5 link	c.812A>C	p.His271Pro	missense_variant	Exon 7 of 9	1		ENSP00000362345.1	Q9BRQ8-1
AIFM2	ENST00000613322.4 link	c.812A>C	p.His271Pro	missense_variant	Exon 8 of 9	5		ENSP00000478931.1	Q9BRQ8-1
AIFM2	ENST00000482166.1 link	n.649A>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251080

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.812A>C (p.H271P) alteration is located in exon 8 (coding exon 7) of the AIFM2 gene. This alteration results from a A to C substitution at nucleotide position 812, causing the histidine (H) at amino acid position 271 to be replaced by a proline (P). 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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

.;T;.

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.7

M;M;M

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.4

D;.;D

REVEL

Benign

0.17

Sift

Benign

0.13

T;.;T

Sift4G

Uncertain

0.030

D;D;D

Polyphen

0.70

P;P;P

Vest4

0.44

MutPred

0.66

Gain of catalytic residue at N269 (P = 0.0964);Gain of catalytic residue at N269 (P = 0.0964);Gain of catalytic residue at N269 (P = 0.0964);

MVP

0.69

MPC

0.35

ClinPred

0.98

GERP RS

3.5

Varity_R

0.87

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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