20-1181012-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001304748.2(TMEM74B):c.607G>A(p.Glu203Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
TMEM74B
NM_001304748.2 missense
NM_001304748.2 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 2.86
Genes affected
TMEM74B (HGNC:15893): (transmembrane protein 74B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
PSMF1 (HGNC:9571): (proteasome inhibitor subunit 1) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a protein that inhibits the activation of the proteasome by the 11S and 19S regulators. Alternative transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM74B | NM_001304748.2 | c.607G>A | p.Glu203Lys | missense_variant | 3/3 | ENST00000429036.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM74B | ENST00000429036.2 | c.607G>A | p.Glu203Lys | missense_variant | 3/3 | 3 | NM_001304748.2 | P1 | |
TMEM74B | ENST00000381894.3 | c.607G>A | p.Glu203Lys | missense_variant | 2/2 | 1 | P1 | ||
PSMF1 | ENST00000381898.5 | c.243-5328C>T | intron_variant | 3 | |||||
PSMF1 | ENST00000652336.1 | c.*364C>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/10 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152180Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250940Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135636
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41AN XY: 727126
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GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74474
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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 submitter | clinical testing | Ambry Genetics | May 09, 2022 | The c.607G>A (p.E203K) alteration is located in exon 2 (coding exon 2) of the TMEM74B gene. This alteration results from a G to A substitution at nucleotide position 607, causing the glutamic acid (E) at amino acid position 203 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0019);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at