8-27287854-C-T

Variant names:

• chr8-27287854-C-T
• rs777582053
• NM_171982.5:c.1178G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_171982.5(TRIM35):​c.1178G>A​(p.Arg393His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000027 (0 hom.)
• Consequence: TRIM35 NM_171982.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

Genes affected

TRIM35 (HGNC:16285): (tripartite motif containing 35) 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 function of this protein has not been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23124161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM35	NM_171982.5	c.1178G>A	p.Arg393His	missense_variant	Exon 6 of 6	ENST00000305364.9	NP_741983.2
TRIM35	XM_047421602.1	c.728G>A	p.Arg243His	missense_variant	Exon 6 of 6		XP_047277558.1
TRIM35	NM_001362813.2	c.*258G>A		3_prime_UTR_variant	Exon 5 of 5		NP_001349742.1
TRIM35	NM_001304495.2	c.*258G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001291424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM35	ENST00000305364.9	c.1178G>A	p.Arg393His	missense_variant	Exon 6 of 6	1	NM_171982.5	ENSP00000301924.4
TRIM35	ENST00000521253	c.*258G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000428770.1
TRIM35	ENST00000521283.1	c.288+182G>A		intron_variant	Intron 4 of 4	2		ENSP00000429356.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460692 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1178G>A (p.R393H) alteration is located in exon 6 (coding exon 6) of the TRIM35 gene. This alteration results from a G to A substitution at nucleotide position 1178, causing the arginine (R) at amino acid position 393 to be replaced by a histidine (H). 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	0.15
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.085
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.77	P
Vest4		0.24
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0507);
MVP		0.57
MPC		0.98
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.090
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs777582053; hg19: chr8-27145371;