14-103928555-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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. 14/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09276828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD9	NM_153046.3	c.46A>C	p.Ile16Leu	missense_variant	Exon 1 of 36	ENST00000409874.9	NP_694591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDRD9	ENST00000409874.9	c.46A>C	p.Ile16Leu	missense_variant	Exon 1 of 36	5	NM_153046.3	ENSP00000387303.4

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

Gnomad4 AFR exome AF: 0.0000414

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000205

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Spermatogenic failure 30 Uncertain:1

Feb 14, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.083
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs868220412; hg19: chr14-104394892;