20-1181269-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001304748.2(TMEM74B):c.350G>A(p.Arg117His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TMEM74B NM_001304748.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01954642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM74B	NM_001304748.2	c.350G>A	p.Arg117His	missense_variant	3/3	ENST00000429036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM74B	ENST00000429036.2	c.350G>A	p.Arg117His	missense_variant	3/3	3	NM_001304748.2	P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250838 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135574

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727040

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74456

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000461

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.350G>A (p.R117H) 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 350, causing the arginine (R) at amino acid position 117 to be replaced by a histidine (H). 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	0.085
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N;.
MutationTaster	Benign	0.62	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.036
Sift	Benign	0.24	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.012	B;.
Vest4		0.15
MVP		0.21
MPC		0.087
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.054
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs145635177; hg19: chr20-1161913;