6-30196547-T-C

Position:

• chr6-30196547-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003449.5(TRIM26):​c.734A>G​(p.Lys245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,458,200 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TRIM26 NM_003449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

TRIM26 (HGNC:12962): (tripartite motif containing 26) The protein encoded by this gene 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. The protein localizes to cytoplasmic bodies. Although the function of the protein is unknown, the RING domain suggests that the protein may have DNA-binding activity. The gene localizes to the major histocompatibility complex (MHC) class I region on chromosome 6. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM26	NM_003449.5	c.734A>G	p.Lys245Arg	missense_variant	6/10	ENST00000454678.7	NP_003440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM26	ENST00000454678.7	c.734A>G	p.Lys245Arg	missense_variant	6/10	1	NM_003449.5	ENSP00000410446.2
TRIM26	ENST00000437089.5	c.734A>G	p.Lys245Arg	missense_variant	5/9	1		ENSP00000395491.1
TRIM26	ENST00000453195.5	c.734A>G	p.Lys245Arg	missense_variant	5/9	1		ENSP00000391879.1
TRIM26	ENST00000416596.5	c.734A>G	p.Lys245Arg	missense_variant	6/6	5		ENSP00000413673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1458200 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 725602

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Sep 08, 2024

The c.734A>G (p.K245R) alteration is located in exon 6 (coding exon 3) of the TRIM26 gene. This alteration results from a A to G substitution at nucleotide position 734, causing the lysine (K) at amino acid position 245 to be replaced by an arginine (R). 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	0.14
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M;M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.36	T;T;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.18
MutPred		0.61		Loss of ubiquitination at K245 (P = 0.0107);Loss of ubiquitination at K245 (P = 0.0107);Loss of ubiquitination at K245 (P = 0.0107);Loss of ubiquitination at K245 (P = 0.0107);
MVP		0.73
MPC		1.1
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.56

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: rs962252073; hg19: chr6-30164324;