chr7-44582121-C-G

Variant names:

• chr7-44582121-C-G
• rs143175119
• NM_182547.4:c.86G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182547.4(TMED4):​c.86G>C​(p.Gly29Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,555,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: TMED4 NM_182547.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.899
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023771077).

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.86G>C	p.Gly29Ala	missense	Exon 1 of 5	NP_872353.2
	TMED4	NM_001303058.2		c.86G>C	p.Gly29Ala	missense	Exon 1 of 4	NP_001289987.1	Q7Z7H5-3
	TMED4	NM_001303059.2		c.86G>C	p.Gly29Ala	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.86G>C	p.Gly29Ala	missense	Exon 1 of 5	ENSP00000404042.2	Q7Z7H5-1
	TMED4	ENST00000481238.1	TSL:1	c.86G>C	p.Gly29Ala	missense	Exon 1 of 4	ENSP00000417443.1	Q7Z7H5-3
	TMED4	ENST00000289577.10	TSL:2	c.86G>C	p.Gly29Ala	missense	Exon 1 of 4	ENSP00000289577.5	F8W7F7

Frequencies

GnomAD3 genomes AF: 0.000893 AC: 136 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00182

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000784 AC: 126 AN: 160620 AF XY: 0.000724

Gnomad AFR exome AF: 0.000336

Gnomad AMR exome AF: 0.000240

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000319

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.000885

GnomAD4 exome AF: 0.00146 AC: 2051 AN: 1403536 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 943 AN XY: 692988

African (AFR) AF: 0.000221 AC: 7 AN: 31690

American (AMR) AF: 0.000305 AC: 11 AN: 36120

Ashkenazi Jewish (ASJ) AF: 0.0000792 AC: 2 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 35986

South Asian (SAS) AF: 0.00 AC: 0 AN: 79890

European-Finnish (FIN) AF: 0.000184 AC: 9 AN: 48846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00183 AC: 1975 AN: 1081886

Other (OTH) AF: 0.000808 AC: 47 AN: 58170

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74504

African (AFR) AF: 0.000168 AC: 7 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000790

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000705 AC: 6

ExAC AF: 0.000353 AC: 39

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	N
PhyloP100		0.90
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.080
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.12
MPC		1.5
ClinPred		0.019	T
GERP RS		3.2
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.58
Mutation Taster		=84/16	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: rs143175119; hg19: chr7-44621720; COSMIC: COSV99071824;