rs3760128

Variant names:

• chr17-75890807-A-G
• rs3760128
• NM_173547.4:c.1526T>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26
• Publications: 48 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173547.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM65	NM_173547.4	MANE Select	c.1526T>C	p.Leu509Pro	missense	Exon 6 of 6	NP_775818.2
	TRIM65	NM_001256124.2		c.1460T>C	p.Leu487Pro	missense	Exon 5 of 5	NP_001243053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM65	ENST00000269383.8	TSL:1 MANE Select	c.1526T>C	p.Leu509Pro	missense	Exon 6 of 6	ENSP00000269383.3
	TRIM65	ENST00000648382.1		n.1095T>C		non_coding_transcript_exon	Exon 5 of 5
	TRIM65	ENST00000591668.5	TSL:2	c.348+470T>C		intron	N/A	ENSP00000465034.1

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

GnomAD2 exomes AF: 0.346 AC: 48163 AN: 139096 AF XY: 0.340

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

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

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

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

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 v4.9

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
PhyloP100		2.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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