Genetic Variant TMED4:p.Gly5Arg (chr7-44582194-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_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. 15/21 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 2401352.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMED4	NM_182547.4 link	c.13G>C	p.Gly5Arg	missense_variant	Exon 1 of 5	ENST00000457408.7	NP_872353.2	Q7Z7H5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMED4	ENST00000457408.7 link	c.13G>C	p.Gly5Arg	missense_variant	Exon 1 of 5	1	NM_182547.4	ENSP00000404042.2		Q7Z7H5-1

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

GnomAD3 exomes

AF:

0.0000556

AC:

AN:

143936

Hom.:

AF XY:

0.0000129

AC XY:

AN XY:

77402

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 SAS 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

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.0000589

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000445

Gnomad4 OTH exome

AF:

0.0000693

GnomAD4 genome

AF:

0.000249

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 12, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.42

DANN

Benign

0.95

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.41

T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.0081

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;.;L

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.030

N;N;N

REVEL

Benign

0.013

Sift

Benign

0.45

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.031

B;.;B

Vest4

0.081

MutPred

0.37

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

MVP

0.13

MPC

1.6

ClinPred

0.049

GERP RS

-1.6

Varity_R

0.026

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over