Variant 10-96327514-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004088.4(DNTT):c.921A>C(p.Glu307Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

DNTT
NM_004088.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.92

Variant links:

Genes affected

DNTT (HGNC:2983): (DNA nucleotidylexotransferase) This gene is a member of the DNA polymerase type-X family and encodes a template-independent DNA polymerase that catalyzes the addition of deoxynucleotides to the 3'-hydroxyl terminus of oligonucleotide primers. In vivo, the encoded protein is expressed in a restricted population of normal and malignant pre-B and pre-T lymphocytes during early differentiation, where it generates antigen receptor diversity by synthesizing non-germ line elements (N-regions) at the junctions of rearranged Ig heavy chain and T cell receptor gene segments. Alternatively spliced transcript variants encoding different isoforms of this gene have been described. [provided by RefSeq, Jul 2008]

DNTT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14372334).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNTT	NM_004088.4 linkuse as main transcript	c.921A>C	p.Glu307Asp	missense_variant	7/11	ENST00000371174.5	NP_004079.3	P04053-1
DNTT	NM_001017520.2 linkuse as main transcript	c.921A>C	p.Glu307Asp	missense_variant	7/11		NP_001017520.1	P04053-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNTT	ENST00000371174.5 linkuse as main transcript	c.921A>C	p.Glu307Asp	missense_variant	7/11	1	NM_004088.4	ENSP00000360216.2		P04053-1
DNTT	ENST00000630152.1 linkuse as main transcript	c.921A>C	p.Glu307Asp	missense_variant	7/11	1		ENSP00000486733.1		P04053-2

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00104

AC:

260

AN:

251064

Hom.:

AF XY:

0.00106

AC XY:

144

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00119

AC:

1743

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

851

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00228

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00106

AC:

162

AN:

152338

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.000979

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000898

AC:

109

EpiCase

AF:

0.00185

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.921A>C (p.E307D) alteration is located in exon 7 (coding exon 7) of the DNTT gene. This alteration results from a A to C substitution at nucleotide position 921, causing the glutamic acid (E) at amino acid position 307 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

Uncertain

0.50

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.28

T;.

Sift4G

Benign

0.16

T;T

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.71

Loss of methylation at R305 (P = 0.1524);Loss of methylation at R305 (P = 0.1524);

MVP

0.63

MPC

0.48

ClinPred

0.078

GERP RS

3.2

Varity_R

0.28

gMVP

0.74

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

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