17-75891068-G-A

Variant names:

• chr17-75891068-G-A
• NM_173547.4:c.1265C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173547.4(TRIM65):​c.1265C>T​(p.Ser422Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM65 NM_173547.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM65	NM_173547.4	MANE Select	c.1265C>T	p.Ser422Phe	missense	Exon 6 of 6	NP_775818.2
	TRIM65	NM_001256124.2		c.1199C>T	p.Ser400Phe	missense	Exon 5 of 5	NP_001243053.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM65	ENST00000269383.8	TSL:1 MANE Select	c.1265C>T	p.Ser422Phe	missense	Exon 6 of 6	ENSP00000269383.3	Q6PJ69
	TRIM65	ENST00000924710.1		c.1304C>T	p.Ser435Phe	missense	Exon 6 of 6	ENSP00000594769.1
	TRIM65	ENST00000924711.1		c.1238C>T	p.Ser413Phe	missense	Exon 5 of 5	ENSP00000594770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459954 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726280

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.73		Loss of disorder (P = 0.0758)
MVP		0.87
MPC		0.75
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.81

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

hg19: chr17-73887149;