NM_153046.3:c.46A>C

Variant names:

• chr14-103928555-A-C
• rs868220412
• NM_153046.3:c.46A>C

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.11
• Publications: 2 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=0.09276828).

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.46A>C	p.Ile16Leu	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.46A>C	p.Ile16Leu	missense	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.46A>C	p.Ile16Leu	missense	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.46A>C	p.Ile16Leu	missense	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000137 AC: 17 AN: 1239384 Hom.: 1 Cov.: 33 AF XY: 0.0000148 AC XY: 9 AN XY: 608616

African (AFR) AF: 0.0000414 AC: 1 AN: 24180

American (AMR) AF: 0.00 AC: 0 AN: 17122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19242

East Asian (EAS) AF: 0.00 AC: 0 AN: 25756

South Asian (SAS) AF: 0.00 AC: 0 AN: 63460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44518

Middle Eastern (MID) AF: 0.00304 AC: 15 AN: 4942

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 991492

Other (OTH) AF: 0.0000205 AC: 1 AN: 48672

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Spermatogenic failure 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.037
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		0.12	B
Vest4		0.29
MutPred		0.35		Loss of catalytic residue at I16 (P = 0.0034)
MVP		0.099
MPC		0.21
ClinPred		0.28	T
GERP RS		3.6
PromoterAI		0.0076	Neutral
Varity_R		0.083
gMVP		0.14
Mutation Taster		=96/4	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: rs868220412; hg19: chr14-104394892;