Variant 15-79314004-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007364.4(TMED3):c.416A>G(p.Gln139Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TMED3
NM_007364.4 missense, splice_region

Scores

Splicing: ADA: 0.9931

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.89

Variant links:

Genes affected

TMED3 (HGNC:28889): (transmembrane p24 trafficking protein 3) Predicted to be involved in Golgi organization; endoplasmic reticulum to Golgi vesicle-mediated transport; and intracellular protein transport. Located in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

TMED3 links:

TMED3 (HGNC:):

TMED3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMED3	NM_007364.4 linkuse as main transcript	c.416A>G	p.Gln139Arg	missense_variant, splice_region_variant	2/3	ENST00000299705.10	NP_031390.1	Q9Y3Q3-1A0A140VKD1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMED3	ENST00000299705.10 linkuse as main transcript	c.416A>G	p.Gln139Arg	missense_variant, splice_region_variant	2/3	1	NM_007364.4	ENSP00000299705.5	Q9Y3Q3-1
TMED3	ENST00000424155.6 linkuse as main transcript	c.416A>G	p.Gln139Arg	missense_variant, splice_region_variant	2/3	3		ENSP00000414983.2	Q9Y3Q3-2
TMED3	ENST00000536821.5 linkuse as main transcript	c.416A>G	p.Gln139Arg	missense_variant, splice_region_variant	2/3	2		ENSP00000446062.1	F5H4M7
TMED3	ENST00000543455.1 linkuse as main transcript	n.416A>G		splice_region_variant, non_coding_transcript_exon_variant	2/4	2		ENSP00000440228.1	G3V1J9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251332

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.416A>G (p.Q139R) alteration is located in exon 2 (coding exon 2) of the TMED3 gene. This alteration results from a A to G substitution at nucleotide position 416, causing the glutamine (Q) at amino acid position 139 to be replaced by an arginine (R). 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

0.31

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;T;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.024

D;D;D

Sift4G

Benign

0.093

T;D;D

Polyphen

0.62

P;.;.

Vest4

0.78

MutPred

0.53

Gain of catalytic residue at Q139 (P = 0.0249);Gain of catalytic residue at Q139 (P = 0.0249);Gain of catalytic residue at Q139 (P = 0.0249);

MVP

0.51

MPC

0.83

ClinPred

0.86

GERP RS

4.7

Varity_R

0.83

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.010

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