Genetic Variant TDRD5:p.Asn280Lys (chr1-179618607-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001199085.3(TDRD5):c.840C>A(p.Asn280Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,585,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N280S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TDRD5
NM_001199085.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.243

Variant links:

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]

TDRD5 links:

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ACMG classification

Classification made for transcript

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=0.093428075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD5	NM_001199085.3 link	c.840C>A	p.Asn280Lys	missense_variant	Exon 5 of 18	ENST00000444136.6	NP_001186014.1	Q8NAT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TDRD5	ENST00000444136.6 link	c.840C>A	p.Asn280Lys	missense_variant	Exon 5 of 18	1	NM_001199085.3	ENSP00000406052.1	Q8NAT2-1
TDRD5	ENST00000294848.12 link	c.840C>A	p.Asn280Lys	missense_variant	Exon 5 of 17	1		ENSP00000294848.8	Q8NAT2-3
TDRD5	ENST00000367614.5 link	c.840C>A	p.Asn280Lys	missense_variant	Exon 5 of 17	2		ENSP00000356586.1	Q8NAT2-3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1433792

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712458

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151706

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74040

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.840C>A (p.N280K) alteration is located in exon 5 (coding exon 4) of the TDRD5 gene. This alteration results from a C to A substitution at nucleotide position 840, causing the asparagine (N) at amino acid position 280 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

Benign

0.25

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.2

DANN

Benign

0.94

DEOGEN2

Benign

0.030

T;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.64

.;T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.093

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.051

Sift

Benign

0.071

T;T;T

Sift4G

Benign

0.88

T;T;T

Polyphen

0.077

B;B;B

Vest4

0.27

MutPred

0.38

Gain of ubiquitination at N280 (P = 0.0146);Gain of ubiquitination at N280 (P = 0.0146);Gain of ubiquitination at N280 (P = 0.0146);

MVP

0.13

MPC

0.25

ClinPred

0.070

GERP RS

-2.4

Varity_R

0.088

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over