Genetic Variant TMED4:p.Gly5Arg (chr7-44582194-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_182547.4(TMED4):c.13G>C(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,544,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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: 𝑓 0.00025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

TMED4
NM_182547.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.70

Publications

0 publications found

Variant links:

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]

TMED4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008057386).

BP6

Variant 7-44582194-C-G is Benign according to our data. Variant chr7-44582194-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2401352.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMED4	NM_182547.4	MANE Select	c.13G>C	p.Gly5Arg	missense	Exon 1 of 5	NP_872353.2
TMED4	NM_001303058.2		c.13G>C	p.Gly5Arg	missense	Exon 1 of 4	NP_001289987.1	Q7Z7H5-3
TMED4	NM_001303059.2		c.13G>C	p.Gly5Arg	missense	Exon 1 of 4	NP_001289988.1	F8W7F7

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000556

AC:

AN:

143936

AF XY:

0.0000129

show subpopulations

Gnomad AFR exome

AF:

0.000919

Gnomad AMR exome

AF:

0.0000441

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000582

AC:

AN:

1392180

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

686950

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

31182

American (AMR)

AF:

0.0000589

AC:

AN:

33984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35684

South Asian (SAS)

AF:

0.00

AC:

AN:

79140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

1077840

Other (OTH)

AF:

0.0000693

AC:

AN:

57746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000249

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41592

American (AMR)

AF:

0.0000653

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00127

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000826

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.42

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.014

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.41

M_CAP

Benign

0.039

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

PhyloP100

-1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.030

REVEL

Benign

0.013

Sift

Benign

0.45

Sift4G

Benign

0.61

Polyphen

0.031

Vest4

0.081

MutPred

0.37

Gain of MoRF binding (P = 2e-04)

MVP

0.13

MPC

1.6

ClinPred

0.049

GERP RS

-1.6

PromoterAI

0.043

Neutral

(source)

Varity_R

0.026

gMVP

0.57

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over