Genetic Variant DNASE1L1:p.Leu7Phe (chrX-154405550-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001303620.2(DNASE1L1):c.19C>T(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DNASE1L1
NM_001303620.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.241

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2043137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1L1	NM_001303620.2 link	c.19C>T	p.Leu7Phe	missense_variant	Exon 2 of 8	ENST00000369807.6	NP_001290549.1	P49184

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L1	ENST00000369807.6 link	c.19C>T	p.Leu7Phe	missense_variant	Exon 2 of 8	1	NM_001303620.2	ENSP00000358822.1		P49184

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1067078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

338892

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19C>T (p.L7F) alteration is located in exon 2 (coding exon 1) of the DNASE1L1 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the leucine (L) at amino acid position 7 to be replaced by a phenylalanine (F). 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

0.069

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.1

DANN

Benign

0.71

DEOGEN2

Benign

0.34

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

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.40

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

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

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

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

REVEL

Benign

0.040

Sift

Benign

0.080

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

Sift4G

Benign

0.40

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

Polyphen

0.0010

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

Vest4

0.072

MutPred

0.40

Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);Loss of disorder (P = 0.1885);

MVP

0.60

MPC

0.30

ClinPred

0.072

GERP RS

-1.9

Varity_R

0.082

gMVP

0.47

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over