rs1816620587

Variant names:

• chr8-124488684-C-G
• rs1816620587
• NM_032026.4:c.804G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-124488684-C-G
• chr8-124488684-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032026.4(TATDN1):​c.804G>C​(p.Glu268Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TATDN1 NM_032026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

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]

ENSG00000253106 (HGNC:):

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TATDN1	NM_032026.4	c.804G>C	p.Glu268Asp	missense_variant	Exon 12 of 12	ENST00000276692.11	NP_114415.1
RNF139	NM_007218.4	c.*1040C>G		downstream_gene_variant		ENST00000303545.4	NP_009149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TATDN1	ENST00000276692.11	c.804G>C	p.Glu268Asp	missense_variant	Exon 12 of 12	1	NM_032026.4	ENSP00000276692.6
RNF139	ENST00000303545.4	c.*1040C>G		downstream_gene_variant		1	NM_007218.4	ENSP00000304051.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448318 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 721316

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100466

Other (OTH) AF: 0.0000167 AC: 1 AN: 59898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.804G>C (p.E268D) alteration is located in exon 12 (coding exon 12) of the TATDN1 gene. This alteration results from a G to C substitution at nucleotide position 804, causing the glutamic acid (E) at amino acid position 268 to be replaced by an aspartic acid (D). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.0060	T
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	.;N;N;D
REVEL	Pathogenic	0.69
Sift	Benign	0.043	.;D;D;D
Sift4G	Uncertain	0.045	D;T;T;T
Polyphen		0.27, 0.93	.;B;.;P
Vest4		0.80
MutPred		0.67		.;.;.;Loss of phosphorylation at S307 (P = 0.3594);
MVP		0.30
MPC		0.026
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.85
gMVP		0.61
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1816620587; hg19: chr8-125500925;