1-222628319-A-T

Position:

• chr1-222628319-A-T

Variant summary

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

The NM_198551.4(MIA3):​c.1099A>T​(p.Thr367Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,746 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (3 hom., cov: 32)
  • Exomes 𝑓: 0.013 (169 hom.)
• Consequence: MIA3 NM_198551.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.388

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004011303).
• BP6: Variant 1-222628319-A-T is Benign according to our data. Variant chr1-222628319-A-T is described in ClinVar as [Benign]. Clinvar id is 782938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0125 (18287/1461378) while in subpopulation NFE AF= 0.0152 (16942/1111876). AF 95% confidence interval is 0.015. There are 169 homozygotes in gnomad4_exome. There are 8814 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIA3	NM_198551.4	c.1099A>T	p.Thr367Ser	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.1099A>T	p.Thr367Ser	missense_variant	4/28	5	NM_198551.4	ENSP00000340900	P1
MIA3	ENST00000470521.1	n.1111A>T		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes AF: 0.00811 AC: 1235 AN: 152250 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00786 AC: 1950 AN: 248132 Hom.: 10 AF XY: 0.00779 AC XY: 1049 AN XY: 134706

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000460

Gnomad FIN exome AF: 0.00543

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.0125 AC: 18287 AN: 1461378 Hom.: 169 Cov.: 33 AF XY: 0.0121 AC XY: 8814 AN XY: 726976

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00596

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00553

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152368 Hom.: 3 Cov.: 32 AF XY: 0.00746 AC XY: 556 AN XY: 74520

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0124 Hom.: 11

Bravo AF: 0.00841

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00300 AC: 11

ESP6500EA AF: 0.0149 AC: 122

ExAC AF: 0.00777 AC: 939

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MIA3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.10
DANN	Benign	0.82
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.020
Sift	Benign	0.23	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.011	B;.
Vest4		0.063
MutPred		0.13		Loss of glycosylation at T367 (P = 0.027);Loss of glycosylation at T367 (P = 0.027);
MVP		0.33
MPC		0.051
ClinPred		0.00082	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.015

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: rs142088763; hg19: chr1-222801661; COSMIC: COSV60513918; COSMIC: COSV60513918;