1-222628013-A-G

Position:

• chr1-222628013-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198551.4(MIA3):​c.793A>G​(p.Lys265Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MIA3 NM_198551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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]

ACMG classification

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=0.16067222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIA3	NM_198551.4	c.793A>G	p.Lys265Glu	missense_variant	4/28	ENST00000344922.10	NP_940953.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIA3	ENST00000344922.10	c.793A>G	p.Lys265Glu	missense_variant	4/28	5	NM_198551.4	ENSP00000340900	P1
MIA3	ENST00000470521.1	n.805A>G		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.793A>G (p.K265E) alteration is located in exon 4 (coding exon 4) of the MIA3 gene. This alteration results from a A to G substitution at nucleotide position 793, causing the lysine (K) at amino acid position 265 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.52	T;T
Polyphen		0.78	P;.
Vest4		0.29
MutPred		0.19		Loss of ubiquitination at K265 (P = 0.0077);Loss of ubiquitination at K265 (P = 0.0077);
MVP		0.48
MPC		0.16
ClinPred		0.53	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.033

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-222801355;