1-117113385-C-T

Variant names:

• chr1-117113385-C-T
• rs199984487
• NM_025188.4:c.1568G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_025188.4(TRIM45):​c.1568G>A​(p.Arg523His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R523C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: TRIM45 NM_025188.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 0 publications found

Genes affected

TRIM45 (HGNC:19018): (tripartite motif containing 45) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to act upstream of or within bone development. Located in cytosol; intercellular bridge; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26583004).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025188.4. 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
	TRIM45	NM_025188.4	MANE Select	c.1568G>A	p.Arg523His	missense	Exon 5 of 6	NP_079464.2	Q9H8W5-1
	TRIM45	NM_001145635.2		c.1514G>A	p.Arg505His	missense	Exon 5 of 6	NP_001139107.1	Q9H8W5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM45	ENST00000256649.9	TSL:1 MANE Select	c.1568G>A	p.Arg523His	missense	Exon 5 of 6	ENSP00000256649.4	Q9H8W5-1
	TRIM45	ENST00000369464.7	TSL:1	c.1514G>A	p.Arg505His	missense	Exon 5 of 6	ENSP00000358476.3	Q9H8W5-2
	TRIM45	ENST00000369461.3	TSL:5	c.1397G>A	p.Arg466His	missense	Exon 6 of 7	ENSP00000358473.3	Q5T2K3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251168 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000514 AC: 75 AN: 1459842 Hom.: 1 Cov.: 30 AF XY: 0.0000592 AC XY: 43 AN XY: 726232

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000236 AC: 1 AN: 4244

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111868

Other (OTH) AF: 0.0000996 AC: 6 AN: 60214

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

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	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.32
Sift	Benign	0.049	D
Sift4G	Uncertain	0.039	D
Polyphen		0.11	B
Vest4		0.32
MutPred		0.43		Gain of methylation at K520 (P = 0.0387)
MVP		0.87
MPC		0.30
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.50
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199984487; hg19: chr1-117656007;