Genetic Variant NAIF1:p.Ala89Thr (chr9-128066837-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_197956.4(NAIF1):c.265G>A(p.Ala89Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NAIF1
NM_197956.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.22

Variant links:

Genes affected

NAIF1 (HGNC:25446): (nuclear apoptosis inducing factor 1) Involved in negative regulation of cell growth and regulation of mitochondrial membrane permeability involved in apoptotic process. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

NAIF1 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
NAIF1	NM_197956.4 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 1 of 2	ENST00000373078.5	NP_931045.1	Q69YI7-1A0A024R887
NAIF1	XM_047422940.1 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 1 of 3		XP_047278896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAIF1	ENST00000373078.5 link	c.265G>A	p.Ala89Thr	missense_variant	Exon 1 of 2	1	NM_197956.4	ENSP00000362170.4		Q69YI7-1
NAIF1	ENST00000466139.1 link	n.84+1286G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247372

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000891

AC:

AN:

1459540

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>A (p.A89T) alteration is located in exon 1 (coding exon 1) of the NAIF1 gene. This alteration results from a G to A substitution at nucleotide position 265, causing the alanine (A) at amino acid position 89 to be replaced by a threonine (T). 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

0.28

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.056

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.64

MutPred

0.39

Loss of helix (P = 0.0033);

MVP

0.51

MPC

1.9

ClinPred

0.87

GERP RS

5.5

Varity_R

0.29

gMVP

0.80

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

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