21-41436028-C-T

Variant names:

• chr21-41436028-C-T
• rs149433993
• NM_002462.5:c.297C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_002462.5(MX1):​c.297C>T​(p.Ser99Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,792 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: MX1 NM_002462.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005107
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

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.297C>T	p.Ser99Ser	splice_region synonymous	Exon 6 of 17	NP_002453.2	P20591-1
	MX1	NM_001144925.2		c.297C>T	p.Ser99Ser	splice_region synonymous	Exon 8 of 19	NP_001138397.1	P20591-1
	MX1	NM_001178046.3		c.297C>T	p.Ser99Ser	splice_region synonymous	Exon 4 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.297C>T	p.Ser99Ser	splice_region synonymous	Exon 6 of 17	ENSP00000381599.3	P20591-1
	MX1	ENST00000455164.6	TSL:1	c.297C>T	p.Ser99Ser	splice_region synonymous	Exon 4 of 15	ENSP00000410523.2	P20591-1
	MX1	ENST00000896042.1		c.297C>T	p.Ser99Ser	splice_region synonymous	Exon 6 of 18	ENSP00000566101.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00177 AC: 444 AN: 250218 AF XY: 0.00154

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00733

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00109 AC: 1591 AN: 1461446 Hom.: 3 Cov.: 31 AF XY: 0.00106 AC XY: 769 AN XY: 726946

African (AFR) AF: 0.000866 AC: 29 AN: 33474

American (AMR) AF: 0.000917 AC: 41 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00810 AC: 432 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000823 AC: 915 AN: 1111748

Other (OTH) AF: 0.00126 AC: 76 AN: 60376

GnomAD4 genome AF: 0.00163 AC: 249 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74500

African (AFR) AF: 0.00120 AC: 50 AN: 41574

American (AMR) AF: 0.00104 AC: 16 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00119

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.74
PhyloP100		-1.1
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.21
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: rs149433993; hg19: chr21-42807955; COSMIC: COSV55820516; COSMIC: COSV55820516;