Genetic Variant NM_033034.3:c.746G>A (chr11-5667710-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_033034.3(TRIM5):c.746G>A(p.Gly249Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,611,612 control chromosomes in the GnomAD database, including 12,698 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2459 hom., cov: 32)

Exomes 𝑓: 0.086 ( 10239 hom. )

Consequence

TRIM5
NM_033034.3 missense, splice_region

Scores

Splicing: ADA: 0.00001234

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.145

Publications

42 publications found

Variant links:

Genes affected

TRIM5 (HGNC:16276): (tripartite motif containing 5) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein forms homo-oligomers via the coilel-coil region and localizes to cytoplasmic bodies. It appears to function as a E3 ubiquitin-ligase and ubiqutinates itself to regulate its subcellular localization. It may play a role in retroviral restriction. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Dec 2009]

TRIM5 links:

ENSG00000239920 (HGNC:):

ENSG00000239920 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=0.0012489855).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM5	NM_033034.3 link	c.746G>A	p.Gly249Asp	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000380034.8	NP_149023.2	Q9C035-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM5	ENST00000380034.8 link	c.746G>A	p.Gly249Asp	missense_variant, splice_region_variant	Exon 5 of 8	2	NM_033034.3	ENSP00000369373.3		Q9C035-1
ENSG00000239920	ENST00000380259.7 link	n.231+10494G>A		intron_variant	Intron 1 of 7	5		ENSP00000369609.3		A0A2U3TZJ3

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21868

AN:

151932

Hom.:

2457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.214

Gnomad ASJ

AF:

0.0543

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.0590

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0577

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.143

AC:

35854

AN:

250190

AF XY:

0.133

show subpopulations

Gnomad AFR exome

AF:

0.265

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.0494

Gnomad EAS exome

AF:

0.444

Gnomad FIN exome

AF:

0.0590

Gnomad NFE exome

AF:

0.0579

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.0862

AC:

125813

AN:

1459562

Hom.:

10239

Cov.:

AF XY:

0.0864

AC XY:

62707

AN XY:

726164

show subpopulations

African (AFR)

AF:

0.262

AC:

8737

AN:

33288

American (AMR)

AF:

0.278

AC:

12319

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

1384

AN:

26086

East Asian (EAS)

AF:

0.421

AC:

16619

AN:

39484

South Asian (SAS)

AF:

0.148

AC:

12739

AN:

85978

European-Finnish (FIN)

AF:

0.0588

AC:

3136

AN:

53368

Middle Eastern (MID)

AF:

0.0847

AC:

488

AN:

5764

European-Non Finnish (NFE)

AF:

0.0573

AC:

63704

AN:

1110942

Other (OTH)

AF:

0.111

AC:

6687

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

5126

10253

15379

20506

25632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2852

5704

8556

11408

14260

<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:

0.144

AC:

21905

AN:

152050

Hom.:

2459

Cov.:

AF XY:

0.147

AC XY:

10966

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.254

AC:

10534

AN:

41414

American (AMR)

AF:

0.214

AC:

3271

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0543

AC:

188

AN:

3464

East Asian (EAS)

AF:

0.431

AC:

2225

AN:

5166

South Asian (SAS)

AF:

0.164

AC:

788

AN:

4812

European-Finnish (FIN)

AF:

0.0590

AC:

625

AN:

10596

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0578

AC:

3930

AN:

68010

Other (OTH)

AF:

0.133

AC:

279

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

849

1698

2547

3396

4245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.0930

Hom.:

5722

Bravo

AF:

0.166

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.255

AC:

1122

ESP6500EA

AF:

0.0584

AC:

502

ExAC

AF:

0.141

AC:

17136

Asia WGS

AF:

0.300

AC:

1040

AN:

3478

EpiCase

AF:

0.0570

EpiControl

AF:

0.0570

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

3.8

(source)

DANN

Benign

0.086

DEOGEN2

Benign

0.00012

T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.58

T;T;T

MetaRNN

Benign

0.0012

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.61

N;N;N

PhyloP100

-0.14

PrimateAI

Benign

0.26

PROVEAN

Benign

4.0

N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.040

MPC

0.064

ClinPred

0.00059

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.062

gMVP

0.15

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0020

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