rs145588689

Variant names:

• chr1-154602065-G-C
• rs145588689
• NM_001111.5:c.577C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-154602065-G-C
• chr1-154602065-G-A
• chr1-154602065-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_001111.5(ADAR):​c.577C>G​(p.Pro193Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,614,176 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002041618: A publication also reported experimental evidence evaluating an impact on protein function, and demonstrated a partial loss of function for the variant protein (Mannion_2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P193L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (5 hom.)
• Consequence: ADAR NM_001111.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:25 U:3 O:2
• Conservation: PhyloP100: 8.43
• Publications: 85 publications found

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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 6

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ADAR-related type 1 interferonopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002041618: A publication also reported experimental evidence evaluating an impact on protein function, and demonstrated a partial loss of function for the variant protein (Mannion_2014).; SCV002768143: "In addition, functional studies show that this variant causes reductions in RNA editing efficiency, but only in compound heterozygote with another pathogenic variant (Mannion, N. M. et al. (2014))."; SCV000321382: knock-in mouse model for this variant supports that it could be a hypomorph variant (PMID: 34343497); SCV002064425: Functional studies in HEK293 cells transfected with the p.Pro193Ala variant exhibit a significant decrease in RNA-editing enzyme activity (Mannion et al., 2014).; SCV000742076: "In one study, functional analysis in HEK293 cells demonstrated that the p.P193A alteration results in significantly decreased RNA-editing activity compared to wildtype (Mannion, 2014)"; SCV000914349: Expression analysis of p.Pro193Ala in HEK293 cells showed a significant reduction in RNA-editing enzyme activity (Mannion et al. 2014).; SCV004105363: This variant has been reported in the compound heterozygous state in multiple families with Aicardi-Goutières syndrome and is predicted to disrupt DNA binding (Rice et al. 2012. PubMed ID: 23001123; Livingston et al. 2015. PubMed ID: 24262145; Piekutowska-Abramczuk et al. 2016. PubMed ID: 28139822).
• PP5: Variant 1-154602065-G-C is Pathogenic according to our data. Variant chr1-154602065-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126395.
• BP4: Computational evidence support a benign effect (MetaRNN=0.037495464). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111.5. 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
	ADAR	NM_001111.5	MANE Select	c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	NP_001102.3	P55265-1
	ADAR	NM_001365045.1		c.604C>G	p.Pro202Ala	missense	Exon 2 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	NP_056655.3	P55265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	ENST00000368474.9	TSL:1 MANE Select	c.577C>G	p.Pro193Ala	missense	Exon 2 of 15	ENSP00000357459.4	P55265-1
	ADAR	ENST00000368471.8	TSL:1	c.-309C>G		5_prime_UTR	Exon 2 of 15	ENSP00000357456.3	P55265-5
	ADAR	ENST00000649724.2		c.607C>G	p.Pro203Ala	missense	Exon 2 of 15	ENSP00000497932.2	A0AAG2TPY2

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00221 AC: 555 AN: 251460 AF XY: 0.00229

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00325 AC: 4748 AN: 1461860 Hom.: 5 Cov.: 89 AF XY: 0.00314 AC XY: 2284 AN XY: 727232

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00304 AC: 136 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86248

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00388 AC: 4310 AN: 1112000

Other (OTH) AF: 0.00253 AC: 153 AN: 60394

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00209 AC XY: 156 AN XY: 74480

African (AFR) AF: 0.000842 AC: 35 AN: 41566

American (AMR) AF: 0.00366 AC: 56 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68016

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00251

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	-	-	Aicardi-Goutieres syndrome 6 (11)
7	-	-	not provided (7)
1	2	-	Symmetrical dyschromatosis of extremities (3)
2	1	-	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (4)
2	-	-	ADAR-related disorder (2)
1	-	-	ADAR-related type 1 interferonopathy (1)
1	-	-	Aicardi Goutieres syndrome (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.037	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.85
MPC		0.87
ClinPred		0.041	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.58
Mutation Taster		=72/28	disease causing (ClinVar)

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: rs145588689; hg19: chr1-154574541; COSMIC: COSV105112956; COSMIC: COSV105112956;