rs782219897

Variant names:

• chrX-154405502-C-T
• rs782219897
• NM_001303620.2:c.67G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001303620.2(DNASE1L1):​c.67G>A​(p.Ala23Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,090,119 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000020 (0 hom. 5 hem.)
• Consequence: DNASE1L1 NM_001303620.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

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.67G>A	p.Ala23Thr	missense	Exon 2 of 8	NP_001290549.1	P49184
	DNASE1L1	NM_001009932.3		c.67G>A	p.Ala23Thr	missense	Exon 4 of 10	NP_001009932.1	P49184
	DNASE1L1	NM_001009933.3		c.67G>A	p.Ala23Thr	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.67G>A	p.Ala23Thr	missense	Exon 2 of 8	ENSP00000358822.1	P49184
	DNASE1L1	ENST00000309585.9	TSL:1	c.67G>A	p.Ala23Thr	missense	Exon 3 of 9	ENSP00000309168.5	P49184
	DNASE1L1	ENST00000369808.7	TSL:1	c.67G>A	p.Ala23Thr	missense	Exon 2 of 8	ENSP00000358823.3	P49184

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000574 AC: 1 AN: 174325 AF XY: 0.0000166

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000202 AC: 22 AN: 1090119 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 5 AN XY: 356515

African (AFR) AF: 0.0000762 AC: 2 AN: 26242

American (AMR) AF: 0.00 AC: 0 AN: 34792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19234

East Asian (EAS) AF: 0.00 AC: 0 AN: 29959

South Asian (SAS) AF: 0.00 AC: 0 AN: 53232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40309

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3982

European-Non Finnish (NFE) AF: 0.0000227 AC: 19 AN: 836715

Other (OTH) AF: 0.0000219 AC: 1 AN: 45654

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.35
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.62		Gain of sheet (P = 0.1208)
MVP		0.57
MPC		0.92
ClinPred		0.87	D
GERP RS		2.5
PromoterAI		-0.030	Neutral
Varity_R		0.31
gMVP		0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

dbSNP: rs782219897; hg19: chrX-153633843;