dbSNP rs3760128: TRIM65:p.Leu509Pro (chr17-75890807-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_173547.4(TRIM65):c.1526T>C(p.Leu509Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,499,910 control chromosomes in the GnomAD database, including 105,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.47 ( 20628 hom., cov: 33)

Exomes 𝑓: 0.34 ( 85216 hom. )

Consequence

TRIM65
NM_173547.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.26

Publications

48 publications found

Variant links:

Genes affected

TRIM65 (HGNC:27316): (tripartite motif containing 65) Predicted to enable zinc ion binding activity. Involved in positive regulation of autophagy. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRIM65 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.7534187E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM65	NM_173547.4 link	c.1526T>C	p.Leu509Pro	missense_variant	Exon 6 of 6	ENST00000269383.8	NP_775818.2	Q6PJ69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM65	ENST00000269383.8 link	c.1526T>C	p.Leu509Pro	missense_variant	Exon 6 of 6	1	NM_173547.4	ENSP00000269383.3		Q6PJ69

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70787

AN:

152030

Hom.:

20572

Cov.:

show subpopulations

Gnomad AFR

AF:

0.831

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.451

GnomAD2 exomes

AF:

0.346

AC:

48163

AN:

139096

AF XY:

0.340

show subpopulations

Gnomad AFR exome

AF:

0.842

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.395

Gnomad EAS exome

AF:

0.216

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

AF:

0.345

AC:

464562

AN:

1347760

Hom.:

85216

Cov.:

AF XY:

0.345

AC XY:

227581

AN XY:

660000

show subpopulations

African (AFR)

AF:

0.855

AC:

24795

AN:

29014

American (AMR)

AF:

0.281

AC:

6475

AN:

23072

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

8484

AN:

21354

East Asian (EAS)

AF:

0.264

AC:

9553

AN:

36220

South Asian (SAS)

AF:

0.360

AC:

25239

AN:

70076

European-Finnish (FIN)

AF:

0.242

AC:

11972

AN:

49420

Middle Eastern (MID)

AF:

0.501

AC:

2644

AN:

5274

European-Non Finnish (NFE)

AF:

0.336

AC:

355060

AN:

1057942

Other (OTH)

AF:

0.367

AC:

20340

AN:

55388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

16347

32695

49042

65390

81737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.466

AC:

70903

AN:

152150

Hom.:

20628

Cov.:

AF XY:

0.455

AC XY:

33844

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.831

AC:

34518

AN:

41522

American (AMR)

AF:

0.331

AC:

5064

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

1421

AN:

3470

East Asian (EAS)

AF:

0.225

AC:

1165

AN:

5168

South Asian (SAS)

AF:

0.349

AC:

1679

AN:

4816

European-Finnish (FIN)

AF:

0.240

AC:

2542

AN:

10588

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23121

AN:

67982

Other (OTH)

AF:

0.455

AC:

963

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1594

3188

4781

6375

7969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.375

Hom.:

23618

Bravo

AF:

0.490

TwinsUK

AF:

0.345

AC:

1280

ALSPAC

AF:

0.339

AC:

1306

ESP6500AA

AF:

0.821

AC:

3605

ESP6500EA

AF:

0.343

AC:

2944

ExAC

AF:

0.303

AC:

35894

Asia WGS

AF:

0.351

AC:

1221

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.046

DEOGEN2

Benign

0.018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00090

LIST_S2

Benign

0.10

MetaRNN

Benign

8.8e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.5

PhyloP100

2.3

PrimateAI

Benign

0.30

PROVEAN

Benign

3.1

REVEL

Benign

0.087

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.052

MPC

0.28

ClinPred

0.0015

GERP RS

3.7

Varity_R

0.028

gMVP

0.43

Mutation Taster

=100/0

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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rs3760128

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