7-44579496-C-A

Variant names:

• chr7-44579496-C-A
• NM_182547.4:c.667G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182547.4(TMED4):​c.667G>T​(p.Ala223Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMED4 NM_182547.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMED4	NM_182547.4	c.667G>T	p.Ala223Ser	missense_variant	Exon 5 of 5	ENST00000457408.7	NP_872353.2
TMED4	NM_001303059.2	c.520G>T	p.Ala174Ser	missense_variant	Exon 4 of 4		NP_001289988.1
TMED4	NM_001303061.2	c.490G>T	p.Ala164Ser	missense_variant	Exon 5 of 5		NP_001289990.1
TMED4	NM_001303062.2	c.490G>T	p.Ala164Ser	missense_variant	Exon 4 of 4		NP_001289991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMED4	ENST00000457408.7	c.667G>T	p.Ala223Ser	missense_variant	Exon 5 of 5	1	NM_182547.4	ENSP00000404042.2
TMED4	ENST00000289577.9	c.520G>T	p.Ala174Ser	missense_variant	Exon 4 of 4	2		ENSP00000289577.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667G>T (p.A223S) alteration is located in exon 5 (coding exon 5) of the TMED4 gene. This alteration results from a G to T substitution at nucleotide position 667, causing the alanine (A) at amino acid position 223 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.36	T;T
Polyphen		0.10	B;.
Vest4		0.59
MutPred		0.42		Gain of disorder (P = 0.0233);.;
MVP		0.15
MPC		1.1
ClinPred		0.95	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.34
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44619095;