NM_001303620.2:c.580C>T

Variant names:

• chrX-154403136-G-A
• rs782174612
• NM_001303620.2:c.580C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001303620.2(DNASE1L1):​c.580C>T​(p.Arg194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,210,167 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 0.000018 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000024 (0 hom. 9 hem.)
• Consequence: DNASE1L1 NM_001303620.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39972878).
• BS2: High Hemizygotes in GnomAdExome4 at 9 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.580C>T	p.Arg194Cys	missense	Exon 7 of 8	NP_001290549.1	P49184
	DNASE1L1	NM_001009932.3		c.580C>T	p.Arg194Cys	missense	Exon 9 of 10	NP_001009932.1	P49184
	DNASE1L1	NM_001009933.3		c.580C>T	p.Arg194Cys	missense	Exon 8 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.580C>T	p.Arg194Cys	missense	Exon 7 of 8	ENSP00000358822.1	P49184
	DNASE1L1	ENST00000309585.9	TSL:1	c.580C>T	p.Arg194Cys	missense	Exon 8 of 9	ENSP00000309168.5	P49184
	DNASE1L1	ENST00000369808.7	TSL:1	c.580C>T	p.Arg194Cys	missense	Exon 7 of 8	ENSP00000358823.3	P49184

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112055 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 9 AN: 183167 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1098112 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 9 AN XY: 363526

African (AFR) AF: 0.0000379 AC: 1 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.000662 AC: 20 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40396

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842136

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112055 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34209

African (AFR) AF: 0.00 AC: 0 AN: 30849

American (AMR) AF: 0.00 AC: 0 AN: 10620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53121

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

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	0.21
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Benign	0.032	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.38		Loss of disorder (P = 0.0134)
MVP		0.88
MPC		1.1
ClinPred		0.63	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.85
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: rs782174612; hg19: chrX-153631477;