Genetic Variant TATDN1:p.Phe293Tyr (chr8-124488610-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032026.4(TATDN1):c.878T>A(p.Phe293Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. F293S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TATDN1
NM_032026.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.33

Publications

0 publications found

Variant links:

Genes affected

TATDN1 (HGNC:24220): (TatD DNase domain containing 1) Predicted to enable 3'-5'-exodeoxyribonuclease activity. Predicted to be involved in DNA metabolic process and nucleic acid phosphodiester bond hydrolysis. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TATDN1 links:

RNF139 (HGNC:17023): (ring finger protein 139) The protein encoded by this gene is a multi-membrane spanning protein containing a RING-H2 finger. This protein is located in the endoplasmic reticulum, and has been shown to possess ubiquitin ligase activity. This gene was found to be interrupted by a t(3:8) translocation in a family with hereditary renal and non-medulary thyroid cancer. Studies of the Drosophila counterpart suggested that this protein may interact with tumor suppressor protein VHL, as well as with COPS5/JAB1, a protein responsible for the degradation of tumor suppressor CDKN1B/P27KIP. [provided by RefSeq, Jul 2008]

RNF139 Gene-Disease associations (from GenCC):

nonpapillary renal cell carcinoma
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

RNF139 links:

ENSG00000253106 (HGNC:):

ENSG00000253106 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TATDN1	NM_032026.4 link	c.878T>A	p.Phe293Tyr	missense_variant	Exon 12 of 12	ENST00000276692.11	NP_114415.1	Q6P1N9-1
RNF139	NM_007218.4 link	c.*966A>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000303545.4	NP_009149.2	Q8WU17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TATDN1	ENST00000276692.11 link	c.878T>A	p.Phe293Tyr	missense_variant	Exon 12 of 12	1	NM_032026.4	ENSP00000276692.6		Q6P1N9-1
RNF139	ENST00000303545.4 link	c.*966A>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_007218.4	ENSP00000304051.4		Q8WU17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.0066

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

2.0

.;M;.

PhyloP100

6.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.3

.;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.023

.;D;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.97

.;D;.

Vest4

0.78

MutPred

0.94

.;Gain of disorder (P = 0.1267);.;

MVP

0.25

MPC

0.070

ClinPred

0.96

GERP RS

4.3

Varity_R

0.67

gMVP

0.59

Mutation Taster

=42/58

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over