NM_007364.4:c.539C>G

Variant names:

• chr15-79322099-C-G
• rs369067846
• NM_007364.4:c.539C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007364.4(TMED3):​c.539C>G​(p.Ser180Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S180F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMED3 NM_007364.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42353228).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007364.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED3	NM_007364.4	MANE Select	c.539C>G	p.Ser180Cys	missense	Exon 3 of 3	NP_031390.1	A0A140VKD1
	TMED3	NM_001330376.2		c.417+8094C>G		intron	N/A	NP_001317305.1	Q9Y3Q3-2
	TMED3	NM_001301203.3		c.417+8094C>G		intron	N/A	NP_001288132.1	F5H4M7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED3	ENST00000299705.10	TSL:1 MANE Select	c.539C>G	p.Ser180Cys	missense	Exon 3 of 3	ENSP00000299705.5	Q9Y3Q3-1
	TMED3	ENST00000964020.1		c.566C>G	p.Ser189Cys	missense	Exon 3 of 3	ENSP00000634079.1
	TMED3	ENST00000896882.1		c.290C>G	p.Ser97Cys	missense	Exon 2 of 2	ENSP00000566941.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.96	D
Vest4		0.40
MutPred		0.61		Loss of disorder (P = 0.0112)
MVP		0.15
MPC		0.34
ClinPred		0.56	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.49

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

Other links and lift over

dbSNP: rs369067846; hg19: chr15-79614441;