X-154405550-G-A

Variant names:

• chrX-154405550-G-A
• NM_001303620.2:c.19C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.241
• Publications: 0 publications found

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]

RPL10 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked, syndromic, 35

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• autism, susceptibility to, X-linked 5

  Inheritance: XL, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2043137).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303620.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L1	NM_001303620.2	MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 2 of 8	NP_001290549.1	P49184
	DNASE1L1	NM_001009932.3		c.19C>T	p.Leu7Phe	missense	Exon 4 of 10	NP_001009932.1	P49184
	DNASE1L1	NM_001009933.3		c.19C>T	p.Leu7Phe	missense	Exon 3 of 9	NP_001009933.1	P49184

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L1	ENST00000369807.6	TSL:1 MANE Select	c.19C>T	p.Leu7Phe	missense	Exon 2 of 8	ENSP00000358822.1	P49184
	DNASE1L1	ENST00000309585.9	TSL:1	c.19C>T	p.Leu7Phe	missense	Exon 3 of 9	ENSP00000309168.5	P49184
	DNASE1L1	ENST00000369808.7	TSL:1	c.19C>T	p.Leu7Phe	missense	Exon 2 of 8	ENSP00000358823.3	P49184

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1067078 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 338892

African (AFR) AF: 0.00 AC: 0 AN: 25757

American (AMR) AF: 0.00 AC: 0 AN: 32571

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18758

East Asian (EAS) AF: 0.00 AC: 0 AN: 28974

South Asian (SAS) AF: 0.00 AC: 0 AN: 50602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 823053

Other (OTH) AF: 0.00 AC: 0 AN: 44667

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.1
DANN	Benign	0.71
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.24
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.040
Sift	Benign	0.080	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.072
MutPred		0.40		Loss of disorder (P = 0.1885)
MVP		0.60
MPC		0.30
ClinPred		0.072	T
GERP RS		-1.9
PromoterAI		0.027	Neutral
Varity_R		0.082
gMVP		0.47
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chrX-153633891;