1-117118624-C-A

Position:

• chr1-117118624-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025188.4(TRIM45):​c.632G>T​(p.Cys211Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TRIM45 NM_025188.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM45	NM_025188.4	c.632G>T	p.Cys211Phe	missense_variant	2/6	ENST00000256649.9	NP_079464.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM45	ENST00000256649.9	c.632G>T	p.Cys211Phe	missense_variant	2/6	1	NM_025188.4	ENSP00000256649	P1
TRIM45	ENST00000369464.7	c.632G>T	p.Cys211Phe	missense_variant	2/6	1		ENSP00000358476
TRIM45	ENST00000369461.3	c.461G>T	p.Cys154Phe	missense_variant	3/7	5		ENSP00000358473
TRIM45	ENST00000485032.1	c.320G>T	p.Cys107Phe	missense_variant	3/3	2		ENSP00000474935

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.632G>T (p.C211F) alteration is located in exon 2 (coding exon 2) of the TRIM45 gene. This alteration results from a G to T substitution at nucleotide position 632, causing the cysteine (C) at amino acid position 211 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;.;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.86		Gain of catalytic residue at C211 (P = 0.0809);Gain of catalytic residue at C211 (P = 0.0809);.;.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.85

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: rs758663757; hg19: chr1-117661246;