14-103928607-C-T

Variant names:

• chr14-103928607-C-T
• rs569772232
• NM_153046.3:c.98C>T

Variant summary

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

The NM_153046.3(TDRD9):​c.98C>T​(p.Pro33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,331,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P33S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TDRD9 NM_153046.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.11521149).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153046.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD9	NM_153046.3	MANE Select	c.98C>T	p.Pro33Leu	missense	Exon 1 of 36	NP_694591.2	Q8NDG6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDRD9	ENST00000409874.9	TSL:5 MANE Select	c.98C>T	p.Pro33Leu	missense	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.98C>T	p.Pro33Leu	missense	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.98C>T	p.Pro33Leu	missense	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000886

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000796 AC: 4 AN: 50226 AF XY: 0.000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000330 AC: 39 AN: 1180782 Hom.: 0 Cov.: 33 AF XY: 0.0000349 AC XY: 20 AN XY: 572964

African (AFR) AF: 0.0000424 AC: 1 AN: 23576

American (AMR) AF: 0.0000645 AC: 1 AN: 15512

Ashkenazi Jewish (ASJ) AF: 0.0000579 AC: 1 AN: 17278

East Asian (EAS) AF: 0.00 AC: 0 AN: 24982

South Asian (SAS) AF: 0.0000192 AC: 1 AN: 51964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41636

Middle Eastern (MID) AF: 0.00168 AC: 7 AN: 4166

European-Non Finnish (NFE) AF: 0.0000209 AC: 20 AN: 955692

Other (OTH) AF: 0.000174 AC: 8 AN: 45976

GnomAD4 genome AF: 0.0000397 AC: 6 AN: 151146 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73856

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000886 AC: 6 AN: 67718

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000475 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.23
MVP		0.20
MPC		0.26
ClinPred		0.070	T
GERP RS		2.7
PromoterAI		-0.038	Neutral
Varity_R		0.030
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs569772232; hg19: chr14-104394944;