chr21-41439705-A-G

Position:

• chr21-41439705-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002462.5(MX1):​c.448A>G​(p.Ile150Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MX1 NM_002462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3106702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MX1	NM_002462.5	c.448A>G	p.Ile150Val	missense_variant	8/17	ENST00000398598.8	NP_002453.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MX1	ENST00000398598.8	c.448A>G	p.Ile150Val	missense_variant	8/17	1	NM_002462.5	ENSP00000381599	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

May 18, 2023

The c.448A>G (p.I150V) alteration is located in exon 10 (coding exon 4) of the MX1 gene. This alteration results from a A to G substitution at nucleotide position 448, causing the isoleucine (I) at amino acid position 150 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	5.2
DANN	Benign	0.73
DEOGEN2	Benign	0.40	T;T;T;.;T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.77	.;T;.;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.076	D
MutationAssessor	Benign	0.68	N;N;N;.;.;.;N
MutationTaster	Benign	0.76	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;.
REVEL	Benign	0.24
Sift	Benign	0.43	T;T;T;T;T;T;.
Sift4G	Benign	0.37	T;T;T;T;T;T;T
Polyphen		0.15	B;B;B;.;.;.;.
Vest4		0.18
MutPred		0.56		Gain of ubiquitination at K145 (P = 0.1446);Gain of ubiquitination at K145 (P = 0.1446);Gain of ubiquitination at K145 (P = 0.1446);Gain of ubiquitination at K145 (P = 0.1446);Gain of ubiquitination at K145 (P = 0.1446);.;Gain of ubiquitination at K145 (P = 0.1446);
MVP		0.84
MPC		0.11
ClinPred		0.38	T
GERP RS		3.4
Varity_R		0.062
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-42811632;