chr13-50012016-T-C

Variant names:

• chr13-50012016-T-C
• NM_213590.3:c.76T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_213590.3(TRIM13):​c.76T>C​(p.Ser26Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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: 6.8e-7 (0 hom.)
• Consequence: TRIM13 NM_213590.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

Genes affected

TRIM13 (HGNC:9976): (tripartite motif containing 13) This gene encodes 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 is located on chromosome 13 within the minimal deletion region for B-cell chronic lymphocytic leukemia. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

DLEU2 (HGNC:13748): (deleted in lymphocytic leukemia 2) This locus represents a microRNA host gene and also produces long alternatively spliced non-coding RNAs. This genome region was observed to be deleted or epigenetically suppressed in leukemia, and was implicated as a negative regulator of cell proliferation. However, an alternative transcript produced at this locus was also found to promote progression through the cell cycle via angiotensin I converting enzyme 2 and cyclin D1. [provided by RefSeq, Dec 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213590.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM13	NM_213590.3	MANE Select	c.76T>C	p.Ser26Pro	missense	Exon 2 of 2	NP_998755.1	O60858-1
	TRIM13	NM_001007278.3		c.85T>C	p.Ser29Pro	missense	Exon 4 of 4	NP_001007279.1	O60858-3
	TRIM13	NM_005798.5		c.76T>C	p.Ser26Pro	missense	Exon 3 of 3	NP_005789.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM13	ENST00000378182.4	TSL:1 MANE Select	c.76T>C	p.Ser26Pro	missense	Exon 2 of 2	ENSP00000367424.3	O60858-1
	TRIM13	ENST00000356017.8	TSL:1	c.85T>C	p.Ser29Pro	missense	Exon 4 of 4	ENSP00000348299.4	O60858-3
	TRIM13	ENST00000420995.6	TSL:1	c.76T>C	p.Ser26Pro	missense	Exon 3 of 3	ENSP00000412943.2	O60858-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.80		Loss of stability (P = 0.1178)
MVP		0.67
MPC		0.59
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.74
Mutation Taster		=8/92	disease causing

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

Other links and lift over

hg19: chr13-50586152;