Genetic Variant NM_015431.4:c.1121C>T (chr1-247876149-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6484 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80197 hom. )

Consequence

TRIM58
NM_015431.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.508

Publications

67 publications found

Variant links:

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]

TRIM58 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TRIM58	NM_015431.4 link	c.1121C>T	p.Thr374Met	missense_variant	Exon 6 of 6	ENST00000366481.4	NP_056246.3	Q8NG06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM58	ENST00000366481.4 link	c.1121C>T	p.Thr374Met	missense_variant	Exon 6 of 6	1	NM_015431.4	ENSP00000355437.3		Q8NG06

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40478

AN:

151960

Hom.:

6489

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.311

AC:

78137

AN:

251394

AF XY:

0.319

show subpopulations

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 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.:

AF XY:

0.329

AC XY:

238965

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0782

AC:

2617

AN:

33480

American (AMR)

AF:

0.293

AC:

13095

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9910

AN:

26136

East Asian (EAS)

AF:

0.209

AC:

8279

AN:

39700

South Asian (SAS)

AF:

0.345

AC:

29742

AN:

86258

European-Finnish (FIN)

AF:

0.347

AC:

18524

AN:

53420

Middle Eastern (MID)

AF:

0.311

AC:

1796

AN:

5768

European-Non Finnish (NFE)

AF:

0.336

AC:

373936

AN:

1111968

Other (OTH)

AF:

0.317

AC:

19175

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

20019

40038

60056

80075

100094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11872

23744

35616

47488

59360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.266

AC:

40470

AN:

152078

Hom.:

6484

Cov.:

AF XY:

0.268

AC XY:

19916

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0850

AC:

3528

AN:

41498

American (AMR)

AF:

0.315

AC:

4810

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

1268

AN:

3470

East Asian (EAS)

AF:

0.231

AC:

1196

AN:

5172

South Asian (SAS)

AF:

0.327

AC:

1572

AN:

4808

European-Finnish (FIN)

AF:

0.350

AC:

3693

AN:

10564

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.344

AC:

23374

AN:

67962

Other (OTH)

AF:

0.264

AC:

559

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1437

2874

4311

5748

7185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.304

Hom.:

17396

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0055

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

-0.51

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.21

Sift4G

Benign

0.21

Polyphen

1.0

Vest4

0.12

MPC

0.39

ClinPred

0.016

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over