Genetic Variant TDRD9:p.Thr15Ala (chr14-103928552-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153046.3(TDRD9):c.43A>G(p.Thr15Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000288 in 1,389,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Publications

0 publications found

Variant links:

Genes affected

TDRD9 (HGNC:20122): (tudor domain containing 9) Predicted to enable RNA binding activity. Involved in spermatogenesis. Located in cytoplasm and nucleus. Implicated in spermatogenic failure 30. [provided by Alliance of Genome Resources, Apr 2022]

TDRD9 Gene-Disease associations (from GenCC):

spermatogenic failure 30
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TDRD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20539925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3 link	c.43A>G	p.Thr15Ala	missense_variant	Exon 1 of 36	ENST00000409874.9	NP_694591.2	Q8NDG6-1Q86WA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD9	ENST00000409874.9 link	c.43A>G	p.Thr15Ala	missense_variant	Exon 1 of 36	5	NM_153046.3	ENSP00000387303.4		Q8NDG6-1

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

66808

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.07e-7

AC:

AN:

1238638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608208

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24140

American (AMR)

AF:

0.00

AC:

AN:

16916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19188

East Asian (EAS)

AF:

0.0000389

AC:

AN:

25714

South Asian (SAS)

AF:

0.00

AC:

AN:

63448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4924

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

991180

Other (OTH)

AF:

0.00

AC:

AN:

48612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150442

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73386

show subpopulations

African (AFR)

AF:

0.0000727

AC:

AN:

41262

American (AMR)

AF:

0.00

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67408

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000334

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43A>G (p.T15A) alteration is located in exon 1 (coding exon 1) of the TDRD9 gene. This alteration results from a A to G substitution at nucleotide position 43, causing the threonine (T) at amino acid position 15 to be replaced by an alanine (A). 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

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

Eigen

Benign

0.00068

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

PhyloP100

4.5

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.99

REVEL

Benign

0.11

Sift

Uncertain

0.012

Sift4G

Benign

0.32

Polyphen

0.77

Vest4

0.33

MVP

0.15

MPC

0.79

ClinPred

0.56

GERP RS

3.6

PromoterAI

0.14

Neutral

(source)

Varity_R

0.13

gMVP

0.61

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over