X-154403308-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001303620.2(DNASE1L1):c.486C>T(p.Tyr162=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,209,837 control chromosomes in the GnomAD database, including 1 homozygotes. There are 198 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., 17 hem., cov: 24)
  • Exomes 𝑓: 0.00046 (1 hom. 181 hem.)
• Consequence: DNASE1L1 NM_001303620.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.830

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022405297).
• BP6: Variant X-154403308-G-A is Benign according to our data. Variant chrX-154403308-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2661802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.83 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNASE1L1	NM_001303620.2	c.486C>T	p.Tyr162=	synonymous_variant	6/8	ENST00000369807.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE1L1	ENST00000369807.6	c.486C>T	p.Tyr162=	synonymous_variant	6/8	1	NM_001303620.2	P1

Frequencies

GnomAD3 genomes AF: 0.000518 AC: 58 AN: 111870 Hom.: 0 Cov.: 24 AF XY: 0.000499 AC XY: 17 AN XY: 34050

Gnomad AFR AF: 0.0000650

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: 0.000164

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000980

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000453 AC: 83 AN: 183177 Hom.: 0 AF XY: 0.000384 AC XY: 26 AN XY: 67687

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.000251

Gnomad NFE exome AF: 0.000844

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000459 AC: 504 AN: 1097915 Hom.: 1 Cov.: 31 AF XY: 0.000498 AC XY: 181 AN XY: 363355

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.000556

Gnomad4 OTH exome AF: 0.000260

GnomAD4 genome AF: 0.000509 AC: 57 AN: 111922 Hom.: 0 Cov.: 24 AF XY: 0.000498 AC XY: 17 AN XY: 34112

Gnomad4 AFR AF: 0.0000649

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000980

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000872 Hom.: 7

Bravo AF: 0.000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

DNASE1L1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.10
Dann	Benign	0.82
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.88	D;D;D;D;D;D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.026
Sift	Benign	0.45	T
Sift4G	Benign	0.47	T
MVP		0.56
ClinPred		0.0076	T
GERP RS		-4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368820912; hg19: chrX-153631649; COSMIC: COSV50010202; COSMIC: COSV50010202;