NM_139243.4:c.275G>A

Variant names:

• chr4-122381094-G-A
• rs146584990
• NM_139243.4:c.275G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_139243.4(ADAD1):​c.275G>A​(p.Arg92His) variant causes a missense change. The variant allele was found at a frequency of 0.000239 in 1,606,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ADAD1 NM_139243.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• Publications: 3 publications found

Genes affected

ADAD1 (HGNC:30713): (adenosine deaminase domain containing 1) Predicted to enable double-stranded RNA adenosine deaminase activity; double-stranded RNA binding activity; and tRNA-specific adenosine deaminase activity. Predicted to be involved in RNA processing and adenosine to inosine editing. Predicted to act upstream of or within spermatid development. Predicted to be located in nucleus. Predicted to be active in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05195254).
• BS2: High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139243.4. 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
	ADAD1	NM_139243.4	MANE Select	c.275G>A	p.Arg92His	missense	Exon 4 of 13	NP_640336.1	Q96M93-1
	ADAD1	NM_001159285.2		c.275G>A	p.Arg92His	missense	Exon 3 of 12	NP_001152757.1	A0A140VKH5
	ADAD1	NM_001159295.2		c.221G>A	p.Arg74His	missense	Exon 3 of 12	NP_001152767.1	Q96M93-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAD1	ENST00000296513.7	TSL:2 MANE Select	c.275G>A	p.Arg92His	missense	Exon 4 of 13	ENSP00000296513.2	Q96M93-1
	ADAD1	ENST00000388724.6	TSL:1	c.275G>A	p.Arg92His	missense	Exon 3 of 12	ENSP00000373376.2	Q96M93-2
	ADAD1	ENST00000388725.2	TSL:2	c.221G>A	p.Arg74His	missense	Exon 3 of 12	ENSP00000373377.2	Q96M93-3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000164 AC: 40 AN: 243596 AF XY: 0.000190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000339

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000245 AC: 357 AN: 1454258 Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 166 AN XY: 723296

African (AFR) AF: 0.0000306 AC: 1 AN: 32722

American (AMR) AF: 0.00 AC: 0 AN: 42314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1110518

Other (OTH) AF: 0.000200 AC: 12 AN: 60108

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74436

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000233 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

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	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.099
Sift	Benign	0.036	D
Sift4G	Uncertain	0.051	T
Polyphen		0.97	D
Vest4		0.15
MVP		0.16
MPC		0.17
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.34
Mutation Taster		=90/10	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: rs146584990; hg19: chr4-123302249; COSMIC: COSV56648003; COSMIC: COSV56648003;