Variant X-154403190-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001303620.2(DNASE1L1):c.526G>A(p.Asp176Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

DNASE1L1
NM_001303620.2 missense, splice_region

Scores

Splicing: ADA: 0.006805

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

DNASE1L1 (HGNC:2957): (deoxyribonuclease 1 like 1) This gene encodes a deoxyribonuclease protein that shows high sequence similarity to DNase I. The encoded protein is localized to the endoplasmic reticulum and modified by N-linked glycosylation. Alternate transcriptional splice variants encoding the same protein have been observed. [provided by RefSeq, Jan 2015]

DNASE1L1 links:

RPL10 (HGNC:10298): (ribosomal protein L10) This gene encodes a ribosomal protein that is a component of the 60S ribosome subunit. The related protein in chicken can bind to c-Jun and can repress c-Jun-mediated transcriptional activation. Some studies have detected an association between variation in this gene and autism spectrum disorders, though others do not detect this relationship. There are multiple pseudogenes of this gene dispersed throughout the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

RPL10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNASE1L1	NM_001303620.2 linkuse as main transcript	c.526G>A	p.Asp176Asn	missense_variant, splice_region_variant	7/8	ENST00000369807.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE1L1	ENST00000369807.6 linkuse as main transcript	c.526G>A	p.Asp176Asn	missense_variant, splice_region_variant	7/8	1	NM_001303620.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182821

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67401

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096959

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362491

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

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

Mar 24, 2023

The c.526G>A (p.D176N) alteration is located in exon 7 (coding exon 6) of the DNASE1L1 gene. This alteration results from a G to A substitution at nucleotide position 526, causing the aspartic acid (D) at amino acid position 176 to be replaced by an asparagine (N). 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

Benign

0.24

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.76

DEOGEN2

Benign

0.28

T;T;T;T;T;T;T;.

FATHMM_MKL

Benign

0.22

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.87

L;L;L;L;L;L;.;.

MutationTaster

Benign

0.92

N;N;N;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

2.3

N;N;N;N;N;N;N;D

REVEL

Benign

0.18

Sift

Benign

0.92

T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;.

Polyphen

0.23

B;B;B;B;B;B;.;.

Vest4

0.10

MutPred

0.68

Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);Gain of methylation at K175 (P = 0.1126);.;

MVP

0.85

MPC

0.28

ClinPred

0.085

GERP RS

4.2

Varity_R

0.081

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0068

dbscSNV1_RF

Benign

0.29

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