11-5603734-A-G

Position:

• chr11-5603734-A-G

Variant summary

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

The NM_001003818.3(TRIM6):​c.506A>G​(p.Gln169Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRIM6 NM_001003818.3 missense, splice_region
• Scores: Splicing: ADA: 0.9742
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

Genes affected

TRIM6 (HGNC:16277): (tripartite motif containing 6) 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, B-box type 1 and B-box type 2 domain, and a coiled-coil region. The protein localizes to the nucleus, but its specific function has not been identified. This gene is mapped to chromosome 11p15, where it resides within a TRIM gene cluster. Alternative splicing results in multiple transcript variants. A read-through transcript from this gene into the downstream TRIM34 gene has also been observed, which results in a fusion product from these neighboring family members. [provided by RefSeq, Oct 2010]

TRIM6-TRIM34 (HGNC:33440): (TRIM6-TRIM34 readthrough) 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. This gene represents a readthrough transcript from genes TRIM6 and TRIM34, and it was described as a splice variant of TRIM34. This gene is mapped to chromosome 11p15, where it resides within a TRIM gene cluster. [provided by RefSeq, Nov 2009]

ENSG00000239920 (HGNC:):

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
TRIM6	NM_001003818.3	c.506A>G	p.Gln169Arg	missense_variant, splice_region_variant	2/8	ENST00000380097.8	NP_001003818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM6	ENST00000380097.8	c.506A>G	p.Gln169Arg	missense_variant, splice_region_variant	2/8	1	NM_001003818.3	ENSP00000369440.3
TRIM6-TRIM34	ENST00000354852.5	c.506A>G	p.Gln169Arg	missense_variant, splice_region_variant	2/14	2		ENSP00000346916.5
ENSG00000239920	ENST00000380259.7	n.*422-8384T>C		intron_variant		5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726966

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Jan 26, 2022

The c.506A>G (p.Q169R) alteration is located in exon 2 (coding exon 2) of the TRIM6 gene. This alteration results from a A to G substitution at nucleotide position 506, causing the glutamine (Q) at amino acid position 169 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	0.060
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T;.;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D;D;D;.;N
REVEL	Benign	0.11
Sift	Benign	0.10	T;T;T;.;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.99	D;P;D;P;B
Vest4		0.32
MutPred		0.26		.;.;Gain of MoRF binding (P = 0.1284);.;Gain of MoRF binding (P = 0.1284);
MVP		0.61
MPC		0.12, 0.046
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1848018807; hg19: chr11-5624964;