1-179592662-G-A

Variant names:

• chr1-179592662-G-A
• rs896902002
• NM_001199085.3:c.47G>A

Variant summary

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

The NM_001199085.3(TDRD5):​c.47G>A​(p.Arg16Lys) 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: TDRD5 NM_001199085.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.10

Genes affected

TDRD5 (HGNC:20614): (tudor domain containing 5) Predicted to be involved in DNA methylation involved in gamete generation; P granule organization; and spermatid development. Predicted to be located in chromatoid body and pi-body. [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, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD5	NM_001199085.3	c.47G>A	p.Arg16Lys	missense_variant	Exon 2 of 18	ENST00000444136.6	NP_001186014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD5	ENST00000444136.6	c.47G>A	p.Arg16Lys	missense_variant	Exon 2 of 18	1	NM_001199085.3	ENSP00000406052.1
TDRD5	ENST00000294848.12	c.47G>A	p.Arg16Lys	missense_variant	Exon 2 of 17	1		ENSP00000294848.8
TDRD5	ENST00000367614.5	c.47G>A	p.Arg16Lys	missense_variant	Exon 2 of 17	2		ENSP00000356586.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47G>A (p.R16K) alteration is located in exon 2 (coding exon 1) of the TDRD5 gene. This alteration results from a G to A substitution at nucleotide position 47, causing the arginine (R) at amino acid position 16 to be replaced by a lysine (K). 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	0.84
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.46		Gain of ubiquitination at R16 (P = 0.03);Gain of ubiquitination at R16 (P = 0.03);Gain of ubiquitination at R16 (P = 0.03);
MVP		0.84
MPC		0.78
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.78
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs896902002; hg19: chr1-179561797; COSMIC: COSV54250255; COSMIC: COSV54250255;