8-124493953-G-T

Variant names:

• chr8-124493953-G-T
• rs999867033
• NM_032026.4:c.671C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_032026.4(TATDN1):​c.671C>A​(p.Pro224His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,605,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TATDN1 NM_032026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78
• Publications: 1 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TATDN1	NM_032026.4	c.671C>A	p.Pro224His	missense_variant	Exon 11 of 12	ENST00000276692.11	NP_114415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TATDN1	ENST00000276692.11	c.671C>A	p.Pro224His	missense_variant	Exon 11 of 12	1	NM_032026.4	ENSP00000276692.6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000824 AC: 2 AN: 242648 AF XY: 0.00000762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453422 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722888

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.0000237 AC: 1 AN: 42260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 84230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109764

Other (OTH) AF: 0.0000500 AC: 3 AN: 59974

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.000524 AC: 8 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000132

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671C>A (p.P224H) alteration is located in exon 11 (coding exon 11) of the TATDN1 gene. This alteration results from a C to A substitution at nucleotide position 671, causing the proline (P) at amino acid position 224 to be replaced by a histidine (H). 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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	4.9	.;H;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.8	.;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.92
MutPred		0.93		.;.;.;Gain of catalytic residue at P260 (P = 0.0254);.;
MVP		0.60
MPC		0.081
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.89
Mutation Taster		=3/97	disease causing

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: rs999867033; hg19: chr8-125506194;