chr4-122380095-A-G

Variant names:

• chr4-122380095-A-G
• rs139643444
• NM_139243.4:c.26A>G

Variant summary

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

The NM_001159295.2(ADAD1):​c.-27-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ADAD1 NM_001159295.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• 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=0.04625687).
• BS2: High AC in GnomAd4 at 19 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159295.2. 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.26A>G	p.Gln9Arg	missense	Exon 3 of 13	NP_640336.1	Q96M93-1
	ADAD1	NM_001159285.2		c.26A>G	p.Gln9Arg	missense	Exon 2 of 12	NP_001152757.1	A0A140VKH5
	ADAD1	NM_001159295.2		c.-27-2A>G		splice_acceptor intron	N/A	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.26A>G	p.Gln9Arg	missense	Exon 3 of 13	ENSP00000296513.2	Q96M93-1
	ADAD1	ENST00000388724.6	TSL:1	c.26A>G	p.Gln9Arg	missense	Exon 2 of 12	ENSP00000373376.2	Q96M93-2
	ADAD1	ENST00000439307.5	TSL:3	c.26A>G	p.Gln9Arg	missense	Exon 2 of 6	ENSP00000397254.1	C9JAT9

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000180 AC: 45 AN: 250232 AF XY: 0.000237

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1460958 Hom.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 726806

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.000135 AC: 6 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1111738

Other (OTH) AF: 0.000116 AC: 7 AN: 60358

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68034

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

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000709

EpiControl AF: 0.000831

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	0.072
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.045	D
Polyphen		0.70	P
Vest4		0.17
MVP		0.27
MPC		0.40
ClinPred		0.067	T
GERP RS		1.4
Varity_R		0.094
gMVP		0.38
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs139643444; hg19: chr4-123301250;