5-115616397-C-G

Variant names:

• chr5-115616397-C-G
• rs753533691
• NM_181836.6:c.487G>C

Variant summary

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

The NM_181836.6(TMED7):​c.487G>C​(p.Asp163His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMED7 NM_181836.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

TMED7 (HGNC:24253): (transmembrane p24 trafficking protein 7) Predicted to be involved in Golgi organization; endoplasmic reticulum to Golgi vesicle-mediated transport; and intracellular protein transport. Located in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

TMED7-TICAM2 (HGNC:33945): (TMED7-TICAM2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring transmembrane emp24 protein transport domain containing 7 (TMED7) and toll-like receptor adaptor molecule 2 (TICAM2) genes. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. This fusion product functions to negatively regulate the adaptor MyD88-independent toll-like receptor 4 pathway. [provided by RefSeq, Nov 2010]

TICAM2-AS1 (HGNC:55575): (TICAM2 antisense RNA 1)

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
TMED7	NM_181836.6	c.487G>C	p.Asp163His	missense_variant	Exon 3 of 3	ENST00000456936.4	NP_861974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMED7	ENST00000456936.4	c.487G>C	p.Asp163His	missense_variant	Exon 3 of 3	1	NM_181836.6	ENSP00000405926.3
TMED7-TICAM2	ENST00000282382.8	c.487G>C	p.Asp163His	missense_variant	Exon 3 of 4	2		ENSP00000282382.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 163 of the TMED7 protein (p.Asp163His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMED7-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.23	T;D;D
Sift4G	Benign	0.099	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.63
MutPred		0.54		Gain of MoRF binding (P = 0.048);Gain of MoRF binding (P = 0.048);Gain of MoRF binding (P = 0.048);
MVP		0.48
MPC		2.1
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.85
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs753533691; hg19: chr5-114952094;