chr19-58544876-C-G

Position:

• chr19-58544876-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005762.3(TRIM28):​c.119C>G​(p.Ala40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000335 in 1,192,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TRIM28 NM_005762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0900

Genes affected

TRIM28 (HGNC:16384): (tripartite motif containing 28) The protein encoded by this gene mediates transcriptional control by interaction with the Kruppel-associated box repression domain found in many transcription factors. The protein localizes to the nucleus and is thought to associate with specific chromatin regions. The protein is a member of the tripartite motif family. This tripartite motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06141606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM28	NM_005762.3	c.119C>G	p.Ala40Gly	missense_variant	1/17	ENST00000253024.10	NP_005753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM28	ENST00000253024.10	c.119C>G	p.Ala40Gly	missense_variant	1/17	1	NM_005762.3	ENSP00000253024.4
TRIM28	ENST00000341753.10	c.119C>G	p.Ala40Gly	missense_variant	1/15	1		ENSP00000342232.5
TRIM28	ENST00000594806.5	c.-222-62C>G		intron_variant		5		ENSP00000473126.1
TRIM28	ENST00000593582.5	c.77-549C>G		intron_variant		3		ENSP00000472586.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000335 AC: 4 AN: 1192956 Hom.: 0 Cov.: 32 AF XY: 0.00000516 AC XY: 3 AN XY: 581860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000790

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000776 AC: 1

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

Jun 09, 2022

The c.119C>G (p.A40G) alteration is located in exon 1 (coding exon 1) of the TRIM28 gene. This alteration results from a C to G substitution at nucleotide position 119, causing the alanine (A) at amino acid position 40 to be replaced by a glycine (G). 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	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.7
DANN	Benign	0.50
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.36	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.091
Sift	Benign	0.63	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0	B;B
Vest4		0.092
MutPred		0.30		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.28
MPC		0.63
ClinPred		0.022	T
GERP RS		-6.1
Varity_R		0.024
gMVP		0.33

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: rs780330642; hg19: chr19-59056243;