10-114204115-A-C

Variant summary

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

The NM_001395205.1(TDRD1):c.1024A>C(p.Lys342Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDRD1 NM_001395205.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

Genes affected

TDRD1 (HGNC:11712): (tudor domain containing 1) This gene encodes a protein containing a tudor domain that is thought to function in the suppression of transposable elements during spermatogenesis. The related protein in mouse forms a complex with piRNAs and Piwi proteins to promote methylation and silencing of target sequences. This gene was observed to be upregulated by ETS transcription factor ERG in prostate tumors. [provided by RefSeq, Sep 2018]

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=0.26376778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDRD1	NM_001395205.1	c.1024A>C	p.Lys342Gln	missense_variant	9/25	ENST00000695399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDRD1	ENST00000695399.1	c.1024A>C	p.Lys342Gln	missense_variant	9/25		NM_001395205.1	P4
TDRD1	ENST00000251864.7	c.1024A>C	p.Lys342Gln	missense_variant	9/26	1		A2
TDRD1	ENST00000369282.5	c.1024A>C	p.Lys342Gln	missense_variant	9/25	5		A2
TDRD1	ENST00000369280.1	c.1024A>C	p.Lys342Gln	missense_variant	9/24	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Sep 21, 2023

The c.1024A>C (p.K342Q) alteration is located in exon 9 (coding exon 8) of the TDRD1 gene. This alteration results from a A to C substitution at nucleotide position 1024, causing the lysine (K) at amino acid position 342 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.79	D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.71	.;P;.
Vest4		0.32
MutPred		0.42		Loss of ubiquitination at K342 (P = 0.0192);Loss of ubiquitination at K342 (P = 0.0192);Loss of ubiquitination at K342 (P = 0.0192);
MVP		0.21
MPC		0.77
ClinPred		0.95	D
GERP RS		4.9
gMVP		0.59

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: rs1589684167; hg19: chr10-115963874;