NM_153046.3:c.421-3T>C

Variant names:

• chr14-103965330-T-C
• rs532678979
• NM_153046.3:c.421-3T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_153046.3(TDRD9):​c.421-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,551,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: TDRD9 NM_153046.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009610
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.56
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-103965330-T-C is Benign according to our data. Variant chr14-103965330-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3035459.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3	c.421-3T>C		splice_region_variant, intron_variant	Intron 3 of 35	ENST00000409874.9	NP_694591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD9	ENST00000409874.9	c.421-3T>C		splice_region_variant, intron_variant	Intron 3 of 35	5	NM_153046.3	ENSP00000387303.4
TDRD9	ENST00000496087.5	n.433-3T>C		splice_region_variant, intron_variant	Intron 4 of 4	4
TDRD9	ENST00000554571.1	n.296-3T>C		splice_region_variant, intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000518 AC: 81 AN: 156482 AF XY: 0.000518

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000568

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000909

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00117 AC: 1641 AN: 1399142 Hom.: 1 Cov.: 31 AF XY: 0.00117 AC XY: 806 AN XY: 690036

African (AFR) AF: 0.000190 AC: 6 AN: 31592

American (AMR) AF: 0.000588 AC: 21 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.00139 AC: 1502 AN: 1078768

Other (OTH) AF: 0.00172 AC: 100 AN: 57994

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74510

African (AFR) AF: 0.000265 AC: 11 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000703

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TDRD9-related disorder Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.6
DANN	Benign	0.62
PhyloP100		1.6
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.034
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: rs532678979; hg19: chr14-104431667;