Genetic Variant TDRD9:p.Ala47Ser (chr14-103928648-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153046.3(TDRD9):c.139G>T(p.Ala47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000478 in 1,255,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Consequence

TDRD9
NM_153046.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060974926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3 link	c.139G>T	p.Ala47Ser	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.139G>T	p.Ala47Ser	missense_variant	Exon 1 of 36	5	NM_153046.3	ENSP00000387303.4		Q8NDG6-1
TDRD9	ENST00000496087.5 link	n.-169G>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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

GnomAD4 exome

AF:

9.06e-7

AC:

AN:

1104228

Hom.:

Cov.:

AF XY:

0.00000189

AC XY:

AN XY:

527876

show subpopulations

African (AFR)

AF:

0.0000458

AC:

AN:

21852

American (AMR)

AF:

0.00

AC:

AN:

8350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13672

East Asian (EAS)

AF:

0.00

AC:

AN:

24030

South Asian (SAS)

AF:

0.00

AC:

AN:

33304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3098

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920556

Other (OTH)

AF:

0.00

AC:

AN:

42738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151186

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73790

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67810

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.635

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.139G>T (p.A47S) alteration is located in exon 1 (coding exon 1) of the TDRD9 gene. This alteration results from a G to T substitution at nucleotide position 139, causing the alanine (A) at amino acid position 47 to be replaced by a serine (S). 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

0.089

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.020

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.34

M_CAP

Benign

0.019

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

PhyloP100

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.22

REVEL

Benign

0.030

Sift

Benign

0.21

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.073

MutPred

0.21

Gain of glycosylation at A47 (P = 0.0086);

MVP

0.040

MPC

0.19

ClinPred

0.080

GERP RS

-5.3

PromoterAI

-0.0072

Neutral

(source)

Varity_R

0.051

gMVP

0.15

Mutation Taster

=99/1

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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14-103928648-G-T

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