10-96318417-C-T

Position:

• chr10-96318417-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004088.4(DNTT):​c.269C>T​(p.Ala90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,814 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (12 hom., cov: 34)
  • Exomes 𝑓: 0.00068 (5 hom.)
• Consequence: DNTT NM_004088.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.587

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003118813).
• BP6: Variant 10-96318417-C-T is Benign according to our data. Variant chr10-96318417-C-T is described in ClinVar as [Benign]. Clinvar id is 776532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00693 (1055/152320) while in subpopulation AFR AF= 0.023 (954/41554). AF 95% confidence interval is 0.0217. There are 12 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNTT	NM_004088.4	c.269C>T	p.Ala90Val	missense_variant	2/11	ENST00000371174.5	NP_004079.3
DNTT	NM_001017520.2	c.269C>T	p.Ala90Val	missense_variant	2/11		NP_001017520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNTT	ENST00000371174.5	c.269C>T	p.Ala90Val	missense_variant	2/11	1	NM_004088.4	ENSP00000360216.2
DNTT	ENST00000630152.1	c.269C>T	p.Ala90Val	missense_variant	2/11	1		ENSP00000486733.1

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1048 AN: 152202 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00191 AC: 478 AN: 250810 Hom.: 5 AF XY: 0.00138 AC XY: 187 AN XY: 135520

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000683 AC: 998 AN: 1461494 Hom.: 5 Cov.: 63 AF XY: 0.000589 AC XY: 428 AN XY: 727032

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00693 AC: 1055 AN: 152320 Hom.: 12 Cov.: 34 AF XY: 0.00669 AC XY: 498 AN XY: 74490

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00126 Hom.: 4

Bravo AF: 0.00812

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00247 AC: 300

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.11	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.19
Sift	Benign	0.29	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;B
Vest4		0.054
MVP		0.74
MPC		0.095
ClinPred		0.0038	T
GERP RS		1.7
Varity_R		0.033
gMVP		0.29

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

Other links and lift over

dbSNP: rs36126211; hg19: chr10-98078174;