NM_001003818.3:c.1185G>C

Variant names:

• chr11-5610976-G-C
• rs1218068816
• NM_001003818.3:c.1185G>C

Variant summary

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

The NM_001003818.3(TRIM6):​c.1185G>C​(p.Trp395Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRIM6 NM_001003818.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36

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:):

TRIM5 (HGNC:16276): (tripartite motif containing 5) 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 forms homo-oligomers via the coilel-coil region and localizes to cytoplasmic bodies. It appears to function as a E3 ubiquitin-ligase and ubiqutinates itself to regulate its subcellular localization. It may play a role in retroviral restriction. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Dec 2009]

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, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM6	NM_001003818.3	c.1185G>C	p.Trp395Cys	missense_variant	Exon 8 of 8	ENST00000380097.8	NP_001003818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM6	ENST00000380097.8	c.1185G>C	p.Trp395Cys	missense_variant	Exon 8 of 8	1	NM_001003818.3	ENSP00000369440.3
TRIM6-TRIM34	ENST00000354852.5	c.985+415G>C		intron_variant	Intron 7 of 13	2		ENSP00000346916.5
ENSG00000239920	ENST00000380259.7	n.*421+15625C>G		intron_variant	Intron 3 of 7	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1185G>C (p.W395C) alteration is located in exon 8 (coding exon 8) of the TRIM6 gene. This alteration results from a G to C substitution at nucleotide position 1185, causing the tryptophan (W) at amino acid position 395 to be replaced by a cysteine (C). 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	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.;D;.;.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.;.
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;.;D
Vest4		0.89
MutPred		0.78		Loss of catalytic residue at A366 (P = 0.0996);.;.;.;.;.;.;.;
MVP		0.81
MPC		0.25
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.75
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1218068816; hg19: chr11-5632206;