7-138554812-T-A

Position:

• chr7-138554812-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015905.3(TRIM24):​c.1376T>A​(p.Phe459Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM24 NM_015905.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

Genes affected

TRIM24 (HGNC:11812): (tripartite motif containing 24) The protein encoded by this gene mediates transcriptional control by interaction with the activation function 2 (AF2) region of several nuclear receptors, including the estrogen, retinoic acid, and vitamin D3 receptors. The protein localizes to nuclear bodies and is thought to associate with chromatin and heterochromatin-associated factors. The protein is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains - a RING, a B-box type 1 and a B-box type 2 - and a coiled-coil region. Two alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TRIM24 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36579546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM24	NM_015905.3	c.1376T>A	p.Phe459Tyr	missense_variant	9/19	ENST00000343526.9	NP_056989.2
TRIM24	NM_003852.4	c.1376T>A	p.Phe459Tyr	missense_variant	9/19		NP_003843.3
TRIM24	XM_024446981.2	c.1319T>A	p.Phe440Tyr	missense_variant	9/19		XP_024302749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM24	ENST00000343526.9	c.1376T>A	p.Phe459Tyr	missense_variant	9/19	1	NM_015905.3	ENSP00000340507.4
TRIM24	ENST00000415680.6	c.1376T>A	p.Phe459Tyr	missense_variant	9/19	1		ENSP00000390829.2
TRIM24	ENST00000493595.1	n.43T>A		non_coding_transcript_exon_variant	1/5	3
TRIM24	ENST00000497516.5	n.1250T>A		non_coding_transcript_exon_variant	9/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 08, 2021

The c.1376T>A (p.F459Y) alteration is located in exon 9 (coding exon 9) of the TRIM24 gene. This alteration results from a T to A substitution at nucleotide position 1376, causing the phenylalanine (F) at amino acid position 459 to be replaced by a tyrosine (Y). 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	Benign	0.27
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.28
Sift	Benign	0.84	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.96	D;P
Vest4		0.52
MutPred		0.29		Loss of methylation at K458 (P = 0.0277);Loss of methylation at K458 (P = 0.0277);
MVP		0.72
MPC		1.1
ClinPred		0.78	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.59

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: rs1387736573; hg19: chr7-138239557;