Variant 1-222628459-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198551.4(MIA3):c.1239A>T(p.Glu413Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MIA3
NM_198551.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00700

Variant links:

Genes affected

MIA3 (HGNC:24008): (MIA SH3 domain ER export factor 3) Enables cargo receptor activity. Involved in several processes, including COPII-coated vesicle cargo loading; cell migration involved in sprouting angiogenesis; and regulation of leukocyte migration. Located in endoplasmic reticulum exit site and endoplasmic reticulum membrane. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MIA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06387249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIA3	NM_198551.4 linkuse as main transcript	c.1239A>T	p.Glu413Asp	missense_variant	4/28	ENST00000344922.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIA3	ENST00000344922.10 linkuse as main transcript	c.1239A>T	p.Glu413Asp	missense_variant	4/28	5	NM_198551.4	P1	Q5JRA6-1
MIA3	ENST00000470521.1 linkuse as main transcript	n.1251A>T		non_coding_transcript_exon_variant	4/7	5
MIA3	ENST00000354906.7 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000809

AC:

AN:

247254

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134134

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460144

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.1239A>T (p.E413D) alteration is located in exon 4 (coding exon 4) of the MIA3 gene. This alteration results from a A to T substitution at nucleotide position 1239, causing the glutamic acid (E) at amino acid position 413 to be replaced by an aspartic acid (D). 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

0.087

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.69

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.0026

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.33

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.047

Sift

Benign

0.33

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.95

P;.

Vest4

0.12

MutPred

0.16

Loss of methylation at K412 (P = 0.1612);Loss of methylation at K412 (P = 0.1612);

MVP

0.40

MPC

0.052

ClinPred

0.088

GERP RS

2.1

Varity_R

0.034

gMVP

0.013

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over