X-154405446-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001303620.2(DNASE1L1):c.123C>A(p.Asp41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,192,507 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000083 (0 hom. 3 hem.)
• Consequence: DNASE1L1 NM_001303620.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.809

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18417263).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNASE1L1	NM_001303620.2	c.123C>A	p.Asp41Glu	missense_variant	2/8	ENST00000369807.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE1L1	ENST00000369807.6	c.123C>A	p.Asp41Glu	missense_variant	2/8	1	NM_001303620.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000353 AC: 4 AN: 113178 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35312

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000176 AC: 3 AN: 170150 Hom.: 0 AF XY: 0.0000355 AC XY: 2 AN XY: 56406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000393

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000834 AC: 9 AN: 1079329 Hom.: 0 Cov.: 31 AF XY: 0.00000859 AC XY: 3 AN XY: 349377

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: 0.00000965

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome AF: 0.0000353 AC: 4 AN: 113178 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000750

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2022

The c.123C>A (p.D41E) alteration is located in exon 2 (coding exon 1) of the DNASE1L1 gene. This alteration results from a C to A substitution at nucleotide position 123, causing the aspartic acid (D) at amino acid position 41 to be replaced by a glutamic acid (E). 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	0.17
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T;T;T;T;.;T
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M;M;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;D;N;D;N
REVEL	Benign	0.17
Sift	Benign	0.077	T;T;T;T;T;T;D;T;D;T
Sift4G	Benign	0.24	T;T;T;T;T;T;D;T;.;.
Polyphen		0.99	D;D;D;D;D;D;.;.;.;.
Vest4		0.045
MutPred		0.38		Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);Loss of MoRF binding (P = 0.1711);
MVP		0.69
MPC		0.28
ClinPred		0.22	T
GERP RS		2.9
Varity_R		0.21
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs781851548; hg19: chrX-153633787;