Genetic Variant TDRD12:p.Val195Ile (chr19-32755992-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366102.1(TDRD12):c.583G>A(p.Val195Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,456,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

TDRD12
NM_001366102.1 missense, splice_region

Scores

Splicing: ADA: 0.2725

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

TDRD12 (HGNC:25044): (tudor domain containing 12) Predicted to enable ATP binding activity; RNA helicase activity; and nucleic acid binding activity. Predicted to be involved in several processes, including gamete generation; gene silencing by RNA; and piRNA metabolic process. Predicted to be part of PET complex. [provided by Alliance of Genome Resources, Apr 2022]

TDRD12 links:

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ACMG classification

Classification made for transcript

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=0.17890659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDRD12	NM_001366102.1 link	c.583G>A	p.Val195Ile	missense_variant, splice_region_variant	Exon 7 of 33	ENST00000639142.2	NP_001353031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TDRD12	ENST00000639142.2 link	c.583G>A	p.Val195Ile	missense_variant, splice_region_variant	Exon 7 of 33	5	NM_001366102.1	ENSP00000492643.2	A0A1W2PRK2
TDRD12	ENST00000444215.6 link	c.583G>A	p.Val195Ile	missense_variant, splice_region_variant	Exon 7 of 28	1		ENSP00000416248.2	Q587J7-1
TDRD12	ENST00000647536.1 link	c.583G>A	p.Val195Ile	missense_variant, splice_region_variant	Exon 7 of 33			ENSP00000496698.1	A0A2R8Y872
TDRD12	ENST00000421545.2 link	c.583G>A	p.Val195Ile	missense_variant, splice_region_variant	Exon 7 of 13	5		ENSP00000390621.2	Q587J7-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

79474

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

43578

show subpopulations

Gnomad AFR exome

AF:

0.000329

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000307

AC:

AN:

1304556

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

640292

show subpopulations

Gnomad4 AFR exome

AF:

0.0000394

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000341

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000370

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583G>A (p.V195I) alteration is located in exon 7 (coding exon 7) of the TDRD12 gene. This alteration results from a G to A substitution at nucleotide position 583, causing the valine (V) at amino acid position 195 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0017

T;.;.

Eigen

Benign

0.053

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.59

N;.;N

REVEL

Benign

0.088

Sift

Pathogenic

0.0

D;.;T

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.096

B;.;.

Vest4

0.086

MVP

0.014

ClinPred

0.92

GERP RS

3.0

Varity_R

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.27

dbscSNV1_RF

Benign

0.38

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over