NM_032026.4:c.746A>T

Variant names:

• chr8-124493878-T-A
• rs750661203
• NM_032026.4:c.746A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032026.4(TATDN1):​c.746A>T​(p.Glu249Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E249G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TATDN1 NM_032026.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• 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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TATDN1	NM_032026.4	c.746A>T	p.Glu249Val	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.746A>T	p.Glu249Val	missense_variant	Exon 11 of 12	1	NM_032026.4	ENSP00000276692.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459584 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726094

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111822

Other (OTH) AF: 0.0000166 AC: 1 AN: 60192

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	.;L;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	.;D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.25	.;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.025, 0.24	.;B;.;B;.
Vest4		0.67
MutPred		0.52		.;.;.;Loss of disorder (P = 0.0227);.;
MVP		0.41
MPC		0.013
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.65
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 2
DS_DL_spliceai		0.41		Position offset: -45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750661203; hg19: chr8-125506119;