21-41443804-G-A

Position:

• chr21-41443804-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002462.5(MX1):​c.946G>A​(p.Gly316Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,238 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (12 hom.)
• Consequence: MX1 NM_002462.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.48

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008124739).
• BP6: Variant 21-41443804-G-A is Benign according to our data. Variant chr21-41443804-G-A is described in ClinVar as [Benign]. Clinvar id is 711249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00796 (1213/152366) while in subpopulation AFR AF= 0.0265 (1102/41572). AF 95% confidence interval is 0.0252. There are 19 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MX1	NM_002462.5	c.946G>A	p.Gly316Arg	missense_variant	11/17	ENST00000398598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MX1	ENST00000398598.8	c.946G>A	p.Gly316Arg	missense_variant	11/17	1	NM_002462.5	P1
	ENST00000411427.3	n.220-1058C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 1215 AN: 152248 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00242 AC: 608 AN: 251486 Hom.: 8 AF XY: 0.00193 AC XY: 262 AN XY: 135916

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000958 AC: 1401 AN: 1461872 Hom.: 12 Cov.: 30 AF XY: 0.000866 AC XY: 630 AN XY: 727244

Gnomad4 AFR exome AF: 0.0268

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00796 AC: 1213 AN: 152366 Hom.: 19 Cov.: 33 AF XY: 0.00772 AC XY: 575 AN XY: 74514

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00168 Hom.: 8

Bravo AF: 0.00920

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00278 AC: 338

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.59	D;D;D;D;.
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	.;D;.;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;.
REVEL	Uncertain	0.36
Sift	Benign	0.045	D;D;D;D;.
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.88	P;P;P;.;.
Vest4		0.34
MutPred		0.65		Gain of phosphorylation at T319 (P = 0.1145);Gain of phosphorylation at T319 (P = 0.1145);Gain of phosphorylation at T319 (P = 0.1145);.;Gain of phosphorylation at T319 (P = 0.1145);
MVP		0.84
MPC		0.20
ClinPred		0.065	T
GERP RS		2.0
Varity_R		0.63
gMVP		0.46

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: rs62623435; hg19: chr21-42815731;