rs190881240

Positions:

• chr1-154589751-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001111.5(ADAR):​c.2668+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,954 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (18 hom.)
• Consequence: ADAR NM_001111.5 splice_region, intron
• Scores: Splicing: ADA: 0.006582
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.196

Genes affected

ADAR (HGNC:225): (adenosine deaminase RNA specific) This gene encodes the enzyme responsible for RNA editing by site-specific deamination of adenosines. This enzyme destabilizes double-stranded RNA through conversion of adenosine to inosine. Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

ADAR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-154589751-A-G is Benign according to our data. Variant chr1-154589751-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292766.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr1-154589751-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00235 (3437/1461864) while in subpopulation SAS AF= 0.00573 (494/86254). AF 95% confidence interval is 0.00531. There are 18 homozygotes in gnomad4_exome. There are 1774 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAR	NM_001111.5	c.2668+6T>C		splice_region_variant, intron_variant		ENST00000368474.9	NP_001102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAR	ENST00000368474.9	c.2668+6T>C		splice_region_variant, intron_variant		1	NM_001111.5	ENSP00000357459.4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151972 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00207 AC: 520 AN: 251294 Hom.: 7 AF XY: 0.00233 AC XY: 317 AN XY: 135814

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00532

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00235 AC: 3437 AN: 1461864 Hom.: 18 Cov.: 32 AF XY: 0.00244 AC XY: 1774 AN XY: 727232

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00573

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74358

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	ADAR: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ADAR NM_001111.4 exon 8 c.2668+6T>C: This variant has not been reported in the literature but is present in 0.5% (161/30782) of South Asian alleles, including 5 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs190881240). This variant is present in ClinVar (Variation ID:292766). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Symmetrical dyschromatosis of extremities Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.6
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0066
dbscSNV1_RF	Benign	0.24
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

Publications

LitVar

Other links and lift over

dbSNP: rs190881240; hg19: chr1-154562227;