X-154402967-G-C

Variant names:

• chrX-154402967-G-C
• rs782157533
• NM_001303620.2:c.749C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001303620.2(DNASE1L1):​c.749C>G​(p.Thr250Arg) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: DNASE1L1 NM_001303620.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.07

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032043785).
• BP6: Variant X-154402967-G-C is Benign according to our data. Variant chrX-154402967-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3841615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1L1	NM_001303620.2	c.749C>G	p.Thr250Arg	missense_variant	Exon 7 of 8	ENST00000369807.6	NP_001290549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L1	ENST00000369807.6	c.749C>G	p.Thr250Arg	missense_variant	Exon 7 of 8	1	NM_001303620.2	ENSP00000358822.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000553 AC: 1 AN: 180995 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

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 Cov.: 32

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.011
DANN	Benign	0.71
DEOGEN2	Benign	0.23	T;T;T;T;T;T
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.45	.;T;.;.;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.032	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N;N;N;N;N;N
REVEL	Benign	0.095
Sift	Benign	0.45	T;T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.089
MutPred		0.27		Loss of glycosylation at T250 (P = 0.0437);Loss of glycosylation at T250 (P = 0.0437);Loss of glycosylation at T250 (P = 0.0437);Loss of glycosylation at T250 (P = 0.0437);Loss of glycosylation at T250 (P = 0.0437);Loss of glycosylation at T250 (P = 0.0437);
MVP		0.92
MPC		0.32
ClinPred		0.057	T
GERP RS		-2.2
Varity_R		0.11
gMVP		0.50

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: rs782157533; hg19: chrX-153631308;