16-69343448-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000288025.4(TMED6):ā€‹c.682A>Gā€‹(p.Asn228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

TMED6
ENST00000288025.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.98
Variant links:
Genes affected
TMED6 (HGNC:28331): (transmembrane p24 trafficking protein 6) Predicted to be involved in Golgi organization; endoplasmic reticulum to Golgi vesicle-mediated transport; and intracellular protein transport. 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.099562585).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMED6NM_144676.4 linkuse as main transcriptc.682A>G p.Asn228Asp missense_variant 4/4 ENST00000288025.4 NP_653277.2 Q8WW62

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMED6ENST00000288025.4 linkuse as main transcriptc.682A>G p.Asn228Asp missense_variant 4/41 NM_144676.4 ENSP00000288025.3 Q8WW62
ENSG00000260371ENST00000563634.1 linkuse as main transcriptc.3-6736A>G intron_variant 4 ENSP00000454500.1 H3BMQ9
ENSG00000259900ENST00000564737.1 linkuse as main transcriptn.465+4340A>G intron_variant 5 ENSP00000462747.1 J3KT08

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251428
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000703
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461886
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 22, 2023The c.682A>G (p.N228D) alteration is located in exon 4 (coding exon 4) of the TMED6 gene. This alteration results from a A to G substitution at nucleotide position 682, causing the asparagine (N) at amino acid position 228 to be replaced by an aspartic acid (D). 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
0.089
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
18
DANN
Benign
0.91
DEOGEN2
Benign
0.0013
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.51
T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
0.90
N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.090
N
REVEL
Benign
0.052
Sift
Benign
0.53
T
Sift4G
Benign
0.64
T
Polyphen
0.0020
B
Vest4
0.13
MutPred
0.42
Loss of catalytic residue at N228 (P = 0.0448);
MVP
0.061
MPC
0.052
ClinPred
0.15
T
GERP RS
4.5
Varity_R
0.072
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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.

Other links and lift over

dbSNP: rs757017185; hg19: chr16-69377351; API