rs3760128

chr17-75890807-A-G

Variant summary

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

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. 14/19 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 0.47 (20628 hom., cov: 33)
  • Exomes 𝑓: 0.34 (85216 hom.)
• Consequence: TRIM65 NM_173547.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TRIM65	NM_173547.4	c.1526T>C	p.Leu509Pro	missense_variant	6/6	ENST00000269383.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM65	ENST00000269383.8	c.1526T>C	p.Leu509Pro	missense_variant	6/6	1	NM_173547.4	P1
TRIM65	ENST00000591668.5	c.349+470T>C		intron_variant		2
TRIM65	ENST00000592642.1	c.210+470T>C		intron_variant		3
TRIM65	ENST00000648382.1	n.1095T>C		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70787 AN: 152030 Hom.: 20572 Cov.: 33

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

GnomAD3 exomes AF: 0.346 AC: 48163 AN: 139096 Hom.: 9957 AF XY: 0.340 AC XY: 25381 AN XY: 74568

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 SAS exome AF: 0.367

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.: 35 AF XY: 0.345 AC XY: 227581 AN XY: 660000

Gnomad4 AFR exome AF: 0.855

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.336

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.466 AC: 70903 AN: 152150 Hom.: 20628 Cov.: 33 AF XY: 0.455 AC XY: 33844 AN XY: 74372

Gnomad4 AFR AF: 0.831

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.455

Alfa AF: 0.366 Hom.: 13856

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	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	10
Dann	Benign	0.046
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00090	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.5	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.087
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.28
ClinPred		0.0015	T
GERP RS		3.7
Varity_R		0.028
gMVP		0.43

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: rs3760128; hg19: chr17-73886888; COSMIC: COSV53933174; COSMIC: COSV53933174;