X-154401914-C-G

Variant names:

• chrX-154401914-C-G
• rs12877
• NM_001303620.2:c.*793G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001303620.2(DNASE1L1):​c.*793G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 111,203 control chromosomes in the GnomAD database, including 7,242 homozygotes. There are 9,679 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7242 hom., 9677 hem., cov: 23)
  • Exomes 𝑓: 0.17 (0 hom. 2 hem.)
• Consequence: DNASE1L1 NM_001303620.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• X-linked syndromic intellectual disability

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (Cadd=0.432).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1L1	NM_001303620.2	c.*793G>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000369807.6	NP_001290549.1
RPL10	NM_006013.5	c.*1060C>G		3_prime_UTR_variant	Exon 7 of 7	ENST00000369817.7	NP_006004.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L1	ENST00000369807.6	c.*793G>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_001303620.2	ENSP00000358822.1
RPL10	ENST00000369817.7	c.*1060C>G		3_prime_UTR_variant	Exon 7 of 7	5	NM_006013.5	ENSP00000358832.2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 33821 AN: 111132 Hom.: 7226 Cov.: 23

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.00731

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0855

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.167 AC: 4 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 2 AN XY: 12

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.190 AC: 4 AN: 21

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.305 AC: 33898 AN: 111179 Hom.: 7242 Cov.: 23 AF XY: 0.289 AC XY: 9677 AN XY: 33431

African (AFR) AF: 0.771 AC: 23436 AN: 30381

American (AMR) AF: 0.222 AC: 2329 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 159 AN: 2649

East Asian (EAS) AF: 0.0941 AC: 336 AN: 3571

South Asian (SAS) AF: 0.169 AC: 451 AN: 2664

European-Finnish (FIN) AF: 0.144 AC: 863 AN: 6005

Middle Eastern (MID) AF: 0.0935 AC: 20 AN: 214

European-Non Finnish (NFE) AF: 0.111 AC: 5891 AN: 52997

Other (OTH) AF: 0.271 AC: 408 AN: 1507

Alfa AF: 0.0647 Hom.: 297

Bravo AF: 0.333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CADD	Benign	0.43
PhyloP100		-1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12877; hg19: -;