chr21-41439805-C-T

Variant names:

• chr21-41439805-C-T
• rs201089600
• NM_002462.5:c.548C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002462.5(MX1):​c.548C>T​(p.Thr183Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,613,896 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: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MX1 NM_002462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

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.548C>T	p.Thr183Ile	missense	Exon 8 of 17	NP_002453.2	P20591-1
	MX1	NM_001144925.2		c.548C>T	p.Thr183Ile	missense	Exon 10 of 19	NP_001138397.1	P20591-1
	MX1	NM_001178046.3		c.548C>T	p.Thr183Ile	missense	Exon 6 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.548C>T	p.Thr183Ile	missense	Exon 8 of 17	ENSP00000381599.3	P20591-1
	MX1	ENST00000455164.6	TSL:1	c.548C>T	p.Thr183Ile	missense	Exon 6 of 15	ENSP00000410523.2	P20591-1
	MX1	ENST00000896042.1		c.548C>T	p.Thr183Ile	missense	Exon 8 of 18	ENSP00000566101.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.0000994 AC: 25 AN: 251484 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000148 AC: 217 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 105 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1111990

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74246

African (AFR) AF: 0.0000242 AC: 1 AN: 41368

American (AMR) AF: 0.000589 AC: 9 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68026

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.000178

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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.61
MVP		0.98
MPC		0.40
ClinPred		0.53	D
GERP RS		4.4
Varity_R		0.61
gMVP		0.78
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs201089600; hg19: chr21-42811732;