15-44758787-T-C

Position:

• chr15-44758787-T-C

Variant summary

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

The ENST00000329464.9(TRIM69):​c.746T>C​(p.Leu249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 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)
• Consequence: TRIM69 ENST00000329464.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.803

Genes affected

TRIM69 (HGNC:17857): (tripartite motif containing 69) This gene encodes a member of the RING-B-box-coiled-coil (RBCC) family and encodes a protein with an N-terminal RING finger motif, a PRY domain and a C-terminal SPRY domain. The mouse ortholog of this gene is specifically expressed in germ cells at the round spermatid stages during spermatogenesis and, when overexpressed, induces apoptosis. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

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
TRIM69	NM_182985.5	c.746T>C	p.Leu249Ser	missense_variant	4/7	ENST00000329464.9	NP_892030.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM69	ENST00000329464.9	c.746T>C	p.Leu249Ser	missense_variant	4/7	1	NM_182985.5	ENSP00000332284	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Apr 05, 2023

The c.746T>C (p.L249S) alteration is located in exon 4 (coding exon 4) of the TRIM69 gene. This alteration results from a T to C substitution at nucleotide position 746, causing the leucine (L) at amino acid position 249 to be replaced by a serine (S). 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	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.0015	T;T;.;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	.;T;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L;L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.39	N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.42	T;T;T;T;T;D
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.083	B;B;.;B;B;.
Vest4		0.33
MutPred		0.39		Gain of disorder (P = 0.0113);Gain of disorder (P = 0.0113);.;.;.;.;
MVP		0.28
MPC		0.012
ClinPred		0.047	T
GERP RS		3.5
Varity_R		0.078
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 16

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45050985;