Genetic Variant NM_002462.5:c.24C>G (chr21-41432094-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002462.5(MX1):c.24C>G(p.Ile8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,798 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I8V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 1 hom. )

Consequence

MX1
NM_002462.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.52

Variant links:

Genes affected

MX1 (HGNC:7532): (MX dynamin like GTPase 1) This gene encodes a guanosine triphosphate (GTP)-metabolizing protein that participates in the cellular antiviral response. The encoded protein is induced by type I and type II interferons and antagonizes the replication process of several different RNA and DNA viruses. There is a related gene located adjacent to this gene on chromosome 21, and there are multiple pseudogenes located in a cluster on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MX1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046801776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MX1	NM_002462.5 link	c.24C>G	p.Ile8Met	missense_variant	Exon 5 of 17	ENST00000398598.8	NP_002453.2	P20591-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MX1	ENST00000398598.8 link	c.24C>G	p.Ile8Met	missense_variant	Exon 5 of 17	1	NM_002462.5	ENSP00000381599.3		P20591-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251402

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.24C>G (p.I8M) alteration is located in exon 7 (coding exon 1) of the MX1 gene. This alteration results from a C to G substitution at nucleotide position 24, causing the isoleucine (I) at amino acid position 8 to be replaced by a methionine (M). 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

0.068

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.28

CADD

Benign

0.013

DANN

Benign

0.34

DEOGEN2

Benign

0.11

T;.;T;T;T;.;T;T;.;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.71

.;T;T;T;.;T;T;T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.047

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.3

L;.;.;L;L;.;.;.;.;.;L

PrimateAI

Benign

0.30

PROVEAN

Benign

0.33

N;N;D;N;N;N;N;N;D;N;.

REVEL

Benign

0.25

Sift

Benign

0.22

T;T;.;T;T;T;T;T;D;T;.

Sift4G

Benign

0.14

T;T;.;T;T;T;T;T;D;T;T

Polyphen

0.022

B;.;.;B;B;.;.;.;.;.;.

Vest4

0.17

MutPred

0.38

Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);Gain of catalytic residue at I8 (P = 0.0026);

MVP

0.55

MPC

0.11

ClinPred

0.14

GERP RS

-5.8

Varity_R

0.058

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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