1-222627891-A-C

Position:

• chr1-222627891-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198551.4(MIA3):​c.671A>C​(p.Gln224Pro) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q224E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIA3 NM_198551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0220

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 (HGNC:):

ACMG classification

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=0.033691585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIA3	NM_198551.4	c.671A>C	p.Gln224Pro	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.671A>C	p.Gln224Pro	missense_variant	4/28	5	NM_198551.4	ENSP00000340900.5
MIA3	ENST00000470521.1	n.683A>C		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Oct 24, 2023

The c.671A>C (p.Q224P) alteration is located in exon 4 (coding exon 4) of the MIA3 gene. This alteration results from a A to C substitution at nucleotide position 671, causing the glutamine (Q) at amino acid position 224 to be replaced by a proline (P). 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	0.066
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.062
DANN	Benign	0.60
DEOGEN2	Benign	0.0034	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.080
Sift	Benign	0.25	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;.
Vest4		0.096
MutPred		0.091		Gain of glycosylation at Q224 (P = 0.0941);Gain of glycosylation at Q224 (P = 0.0941);
MVP		0.15
MPC		0.063
ClinPred		0.074	T
GERP RS		-11
Varity_R		0.072
gMVP		0.042

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: chr1-222801233;