21-41435950-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002462.5(MX1):c.219C>G(p.Ile73Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MX1 NM_002462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.286

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MX1	NM_002462.5	c.219C>G	p.Ile73Met	missense_variant	6/17	ENST00000398598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MX1	ENST00000398598.8	c.219C>G	p.Ile73Met	missense_variant	6/17	1	NM_002462.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

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: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Sep 23, 2023

The c.219C>G (p.I73M) alteration is located in exon 8 (coding exon 2) of the MX1 gene. This alteration results from a C to G substitution at nucleotide position 219, causing the isoleucine (I) at amino acid position 73 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D;D;.;T;T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.73	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;.;.;.
Vest4		0.81
MutPred		0.87		Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);Gain of disorder (P = 0.0856);
MVP		0.96
MPC		0.54
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.79
gMVP		0.87

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: rs545554440; hg19: chr21-42807877;