chr21-41432094-C-G

Variant names:

• chr21-41432094-C-G
• rs182413451
• NM_002462.5:c.24C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 17/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046801776).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002462.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MX1	NM_002462.5	MANE Select	c.24C>G	p.Ile8Met	missense	Exon 5 of 17	NP_002453.2	P20591-1
	MX1	NM_001144925.2		c.24C>G	p.Ile8Met	missense	Exon 7 of 19	NP_001138397.1	P20591-1
	MX1	NM_001178046.3		c.24C>G	p.Ile8Met	missense	Exon 3 of 15	NP_001171517.1	P20591-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MX1	ENST00000398598.8	TSL:1 MANE Select	c.24C>G	p.Ile8Met	missense	Exon 5 of 17	ENSP00000381599.3	P20591-1
	MX1	ENST00000455164.6	TSL:1	c.24C>G	p.Ile8Met	missense	Exon 3 of 15	ENSP00000410523.2	P20591-1
	MX1	ENST00000896042.1		c.24C>G	p.Ile8Met	missense	Exon 5 of 18	ENSP00000566101.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251402 AF XY: 0.0000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461798 Hom.: 1 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.013
DANN	Benign	0.34
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Benign	0.14	T
Polyphen		0.022	B
Vest4		0.17
MutPred		0.38		Gain of catalytic residue at I8 (P = 0.0026)
MVP		0.55
MPC		0.11
ClinPred		0.14	T
GERP RS		-5.8
PromoterAI		0.0026	Neutral
Varity_R		0.058
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs182413451; hg19: chr21-42804021;