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GeneBe

1-222628501-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198551.4(MIA3):c.1281A>T(p.Lys427Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,362 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: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MIA3
NM_198551.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11609405).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MIA3NM_198551.4 linkuse as main transcriptc.1281A>T p.Lys427Asn missense_variant 4/28 ENST00000344922.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MIA3ENST00000344922.10 linkuse as main transcriptc.1281A>T p.Lys427Asn missense_variant 4/285 NM_198551.4 P1Q5JRA6-1
MIA3ENST00000354906.7 linkuse as main transcriptc.30A>T p.Lys10Asn missense_variant 1/135
MIA3ENST00000470521.1 linkuse as main transcriptn.1293A>T non_coding_transcript_exon_variant 4/75

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248886
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135048
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:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461362
Hom.:
0
Cov.:
33
AF XY:
0.0000165
AC XY:
12
AN XY:
726982
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000827
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsMar 01, 2024The c.1281A>T (p.K427N) 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 1281, causing the lysine (K) at amino acid position 427 to be replaced by an asparagine (N). 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
0.21
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
Cadd
Benign
12
Dann
Benign
0.96
DEOGEN2
Benign
0.016
T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.38
N
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.070
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.15
T;T
Polyphen
0.65
P;.
Vest4
0.14
MutPred
0.30
Loss of ubiquitination at K427 (P = 6e-04);Loss of ubiquitination at K427 (P = 6e-04);
MVP
0.30
MPC
0.26
ClinPred
0.31
T
GERP RS
-3.4
Varity_R
0.089
gMVP
0.022

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.

Other links and lift over

dbSNP: rs761103413; hg19: chr1-222801843; API