13-60467269-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001146070.2(TDRD3):c.385C>T(p.Leu129Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TDRD3 NM_001146070.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

Genes affected

TDRD3 (HGNC:20612): (tudor domain containing 3) Enables chromatin binding activity; methylated histone binding activity; and transcription coactivator activity. Predicted to be involved in chromatin organization and positive regulation of transcription, DNA-templated. Located in Golgi apparatus; cytosol; and nucleoplasm. Colocalizes with exon-exon junction complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD3	NM_001146070.2	c.385C>T	p.Leu129Phe	missense_variant	5/14	ENST00000377881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD3	ENST00000377881.8	c.385C>T	p.Leu129Phe	missense_variant	5/14	1	NM_001146070.2	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

Dec 03, 2021

The c.385C>T (p.L129F) alteration is located in exon 5 (coding exon 5) of the TDRD3 gene. This alteration results from a C to T substitution at nucleotide position 385, causing the leucine (L) at amino acid position 129 to be replaced by a phenylalanine (F). 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	0.60
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T;.;T;T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N;N;N;.;.;D
REVEL	Pathogenic	0.73
Sift	Benign	0.22	T;T;T;T;.;.;T
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.90
MutPred		0.49		Gain of methylation at K35 (P = 0.0308);Gain of methylation at K35 (P = 0.0308);.;Gain of methylation at K35 (P = 0.0308);Gain of methylation at K35 (P = 0.0308);Gain of methylation at K35 (P = 0.0308);Gain of methylation at K35 (P = 0.0308);
MVP		0.98
MPC		0.68
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-61041403;