7-44582194-C-T

Variant names:

• chr7-44582194-C-T
• NM_182547.4:c.13G>A
• TMED4 p.Gly5Arg

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182547.4(TMED4):​c.13G>A​(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G5W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMED4 NM_182547.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 0 publications found

Genes affected

TMED4 (HGNC:22301): (transmembrane p24 trafficking protein 4) Involved in positive regulation of I-kappaB kinase/NF-kappaB signaling. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in several cellular components, including COPII-coated ER to Golgi transport vesicle; Golgi apparatus; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050008774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182547.4. 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
	TMED4	NM_182547.4	MANE Select	c.13G>A	p.Gly5Arg	missense	Exon 1 of 5	NP_872353.2
	TMED4	NM_001303058.2		c.13G>A	p.Gly5Arg	missense	Exon 1 of 4	NP_001289987.1	Q7Z7H5-3
	TMED4	NM_001303059.2		c.13G>A	p.Gly5Arg	missense	Exon 1 of 4	NP_001289988.1	F8W7F7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMED4	ENST00000457408.7	TSL:1 MANE Select	c.13G>A	p.Gly5Arg	missense	Exon 1 of 5	ENSP00000404042.2	Q7Z7H5-1
	TMED4	ENST00000481238.1	TSL:1	c.13G>A	p.Gly5Arg	missense	Exon 1 of 4	ENSP00000417443.1	Q7Z7H5-3
	TMED4	ENST00000289577.10	TSL:2	c.13G>A	p.Gly5Arg	missense	Exon 1 of 4	ENSP00000289577.5	F8W7F7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1392182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 686950

African (AFR) AF: 0.00 AC: 0 AN: 31184

American (AMR) AF: 0.00 AC: 0 AN: 33984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35684

South Asian (SAS) AF: 0.00 AC: 0 AN: 79140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077840

Other (OTH) AF: 0.00 AC: 0 AN: 57746

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.53
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		-1.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.012
Sift	Benign	0.45	T
Sift4G	Benign	0.61	T
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.57
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-44621793;