chr1-154597836-A-G

Variant names:

• chr1-154597836-A-G
• rs150171059
• NM_001111.5:c.1926T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365045.1(ADAR):​c.1953T>C​(p.His651His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,142 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: ADAR NM_001365045.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.102
• Publications: 0 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

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• dyschromatosis symmetrica hereditaria

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Aicardi-Goutieres syndrome 6

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-154597836-A-G is Benign according to our data. Variant chr1-154597836-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.102 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00133 (202/152280) while in subpopulation AMR AF = 0.00235 (36/15298). AF 95% confidence interval is 0.00175. There are 1 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365045.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	NM_001111.5	MANE Select	c.1926T>C	p.His642His	synonymous	Exon 4 of 15	NP_001102.3
	ADAR	NM_001365045.1		c.1953T>C	p.His651His	synonymous	Exon 4 of 15	NP_001351974.1
	ADAR	NM_015840.4		c.1926T>C	p.His642His	synonymous	Exon 4 of 15	NP_056655.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAR	ENST00000368474.9	TSL:1 MANE Select	c.1926T>C	p.His642His	synonymous	Exon 4 of 15	ENSP00000357459.4
	ADAR	ENST00000368471.8	TSL:1	c.1041T>C	p.His347His	synonymous	Exon 4 of 15	ENSP00000357456.3
	ADAR	ENST00000649724.2		c.1956T>C	p.His652His	synonymous	Exon 4 of 15	ENSP00000497932.2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00134 AC: 338 AN: 251454 AF XY: 0.00142

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00169 AC: 2468 AN: 1461862 Hom.: 8 Cov.: 32 AF XY: 0.00171 AC XY: 1240 AN XY: 727238

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00144 AC: 124 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5752

European-Non Finnish (NFE) AF: 0.00193 AC: 2148 AN: 1112000

Other (OTH) AF: 0.00146 AC: 88 AN: 60396

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74468

African (AFR) AF: 0.000505 AC: 21 AN: 41550

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68022

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00138

EpiCase AF: 0.00185

EpiControl AF: 0.00231

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Aicardi-Goutieres syndrome 6 (1)
-	-	1	Symmetrical dyschromatosis of extremities (1)
-	-	1	Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.6
DANN	Benign	0.53
PhyloP100		0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs150171059; hg19: chr1-154570312;