rs3811444

Positions:

• chr1-247876149-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015431.4(TRIM58):​c.1121C>T​(p.Thr374Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,613,926 control chromosomes in the GnomAD database, including 86,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6484 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80197 hom.)
• Consequence: TRIM58 NM_015431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.508

Genes affected

TRIM58 (HGNC:24150): (tripartite motif containing 58) Predicted to enable dynein heavy chain binding activity; dynein intermediate chain binding activity; and ubiquitin protein ligase activity. Predicted to be involved in several processes, including positive regulation of erythrocyte enucleation; protein ubiquitination; and regulation of nuclear migration along microtubule. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005764544).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM58	NM_015431.4	c.1121C>T	p.Thr374Met	missense_variant	6/6	ENST00000366481.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM58	ENST00000366481.4	c.1121C>T	p.Thr374Met	missense_variant	6/6	1	NM_015431.4	P1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40478 AN: 151960 Hom.: 6489 Cov.: 32

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.311 AC: 78137 AN: 251394 Hom.: 12944 AF XY: 0.319 AC XY: 43401 AN XY: 135870

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.379

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.348

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.326 AC: 477074 AN: 1461848 Hom.: 80197 Cov.: 71 AF XY: 0.329 AC XY: 238965 AN XY: 727224

Gnomad4 AFR exome AF: 0.0782

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.347

Gnomad4 NFE exome AF: 0.336

Gnomad4 OTH exome AF: 0.317

GnomAD4 genome AF: 0.266 AC: 40470 AN: 152078 Hom.: 6484 Cov.: 32 AF XY: 0.268 AC XY: 19916 AN XY: 74326

Gnomad4 AFR AF: 0.0850

Gnomad4 AMR AF: 0.315

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.264

Alfa AF: 0.307 Hom.: 5656

Bravo AF: 0.252

TwinsUK AF: 0.320 AC: 1185

ALSPAC AF: 0.322 AC: 1241

ESP6500AA AF: 0.0887 AC: 391

ESP6500EA AF: 0.346 AC: 2974

ExAC AF: 0.305 AC: 37013

Asia WGS AF: 0.245 AC: 855 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.12
MPC		0.39
ClinPred		0.016	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.26

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: rs3811444; hg19: chr1-248039451; COSMIC: COSV63569336;