14-103928555-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153046.3(TDRD9):​c.46A>G​(p.Ile16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,239,384 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I16L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TDRD9 NM_153046.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 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: 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=0.072239876).

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>G	p.Ile16Val	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>G	p.Ile16Val	missense	Exon 1 of 36	ENSP00000387303.4	Q8NDG6-1
	TDRD9	ENST00000967811.1		c.46A>G	p.Ile16Val	missense	Exon 1 of 35	ENSP00000637870.1
	TDRD9	ENST00000967812.1		c.46A>G	p.Ile16Val	missense	Exon 1 of 35	ENSP00000637871.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1239384 Hom.: 0 Cov.: 33 AF XY: 0.00000329 AC XY: 2 AN XY: 608616

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 4942

European-Non Finnish (NFE) AF: 0.00000202 AC: 2 AN: 991492

Other (OTH) AF: 0.00 AC: 0 AN: 48672

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.026
Sift	Benign	0.28	T
Sift4G	Benign	0.70	T
Polyphen		0.0090	B
Vest4		0.26
MutPred		0.25		Loss of catalytic residue at I16 (P = 0.0225)
MVP		0.081
MPC		0.18
ClinPred		0.22	T
GERP RS		3.6
PromoterAI		0.013	Neutral
Varity_R		0.051
gMVP		0.099
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: rs868220412; hg19: chr14-104394892;