15-79313812-A-G

Variant names:

• chr15-79313812-A-G
• rs868343566
• NM_007364.4:c.224A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007364.4(TMED3):​c.224A>G​(p.Asn75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. N75I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TMED3 NM_007364.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079358935).

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.224A>G	p.Asn75Ser	missense	Exon 2 of 3	NP_031390.1	A0A140VKD1
	TMED3	NM_001330376.2		c.224A>G	p.Asn75Ser	missense	Exon 2 of 3	NP_001317305.1	Q9Y3Q3-2
	TMED3	NM_001301203.3		c.224A>G	p.Asn75Ser	missense	Exon 2 of 3	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.224A>G	p.Asn75Ser	missense	Exon 2 of 3	ENSP00000299705.5	Q9Y3Q3-1
	TMED3	ENST00000964020.1		c.224A>G	p.Asn75Ser	missense	Exon 2 of 3	ENSP00000634079.1
	TMED3	ENST00000424155.6	TSL:3	c.224A>G	p.Asn75Ser	missense	Exon 2 of 3	ENSP00000414983.2	Q9Y3Q3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 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: 26136

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: 0.0000144 AC: 16 AN: 1112010

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.22
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.022
Sift	Benign	0.51	T
Sift4G	Benign	0.65	T
Polyphen		0.030	B
Vest4		0.061
MutPred		0.38		Gain of disorder (P = 0.0668)
MVP		0.13
MPC		0.28
ClinPred		0.19	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.32
Mutation Taster		=95/5	polymorphism

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: rs868343566; hg19: chr15-79606154;