15-79311343-G-C

Position:

• chr15-79311343-G-C

Variant summary

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

The NM_007364.4(TMED3):​c.94G>C​(p.Glu32Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,270 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMED3 NM_007364.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMED3	NM_007364.4	c.94G>C	p.Glu32Gln	missense_variant	1/3	ENST00000299705.10	NP_031390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMED3	ENST00000299705.10	c.94G>C	p.Glu32Gln	missense_variant	1/3	1	NM_007364.4	ENSP00000299705.5
TMED3	ENST00000424155.6	c.94G>C	p.Glu32Gln	missense_variant	1/3	3		ENSP00000414983.2
TMED3	ENST00000536821.5	c.94G>C	p.Glu32Gln	missense_variant	1/3	2		ENSP00000446062.1
TMED3	ENST00000543455.1	n.94G>C		non_coding_transcript_exon_variant	1/4	2		ENSP00000440228.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459270 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725810

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.94G>C (p.E32Q) alteration is located in exon 1 (coding exon 1) of the TMED3 gene. This alteration results from a G to C substitution at nucleotide position 94, causing the glutamic acid (E) at amino acid position 32 to be replaced by a glutamine (Q). 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	0.051	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.57
MutPred		0.54		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.43
MPC		1.0
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.47

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: rs1373361226; hg19: chr15-79603685;