6-30198977-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_003449.5(TRIM26):c.127G>A(p.Val43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: TRIM26 NM_003449.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.911

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRIM26
• BP4: Computational evidence support a benign effect (MetaRNN=0.011724532).
• BP6: Variant 6-30198977-C-T is Benign according to our data. Variant chr6-30198977-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3182320.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM26	NM_003449.5	c.127G>A	p.Val43Ile	missense_variant	4/10	ENST00000454678.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM26	ENST00000454678.7	c.127G>A	p.Val43Ile	missense_variant	4/10	1	NM_003449.5	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000114 AC: 28 AN: 246276 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134262

Gnomad AFR exome AF: 0.000796

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1460346 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 39 AN XY: 726398

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.0000895

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: 0.0000432

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152182 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74410

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000119 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	1.2
Dann	Benign	0.44
DEOGEN2	Benign	0.021	T;T;T;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.17	N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.81	T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;.;.;T
Polyphen		0.79	P;P;P;.;.;.
Vest4		0.035
MVP		0.12
MPC		0.89
ClinPred		0.019	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.40

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: rs141679609; hg19: chr6-30166754;