Genetic Variant TDRD9:p.Ile16Leu (chr14-103928555-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_153046.3(TDRD9):c.46A>C(p.Ile16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,239,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.11

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09276828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3 link	c.46A>C	p.Ile16Leu	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.46A>C	p.Ile16Leu	missense_variant	Exon 1 of 36	5	NM_153046.3	ENSP00000387303.4		Q8NDG6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1239384

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

608616

show subpopulations

African (AFR)

AF:

0.0000414

AC:

AN:

24180

American (AMR)

AF:

0.00

AC:

AN:

17122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19242

East Asian (EAS)

AF:

0.00

AC:

AN:

25756

South Asian (SAS)

AF:

0.00

AC:

AN:

63460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44518

Middle Eastern (MID)

AF:

0.00304

AC:

AN:

4942

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

991492

Other (OTH)

AF:

0.0000205

AC:

AN:

48672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Spermatogenic failure 30

Uncertain:1

Feb 14, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.091

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.48

M_CAP

Benign

0.052

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

PhyloP100

2.1

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.29

REVEL

Benign

0.037

Sift

Benign

0.20

Sift4G

Benign

0.42

Polyphen

0.12

Vest4

0.29

MutPred

0.35

Loss of catalytic residue at I16 (P = 0.0034);

MVP

0.099

MPC

0.21

ClinPred

0.28

GERP RS

3.6

PromoterAI

0.0076

Neutral

(source)

Varity_R

0.083

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

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14-103928555-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over