NM_139243.4:c.355A>G

Variant names:

• chr4-122381174-A-G
• rs200548828
• NM_139243.4:c.355A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_139243.4(ADAD1):​c.355A>G​(p.Thr119Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,552,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ADAD1 NM_139243.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08197868).
• BS2: High AC in GnomAdExome4 at 60 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.355A>G	p.Thr119Ala	missense	Exon 4 of 13	NP_640336.1	Q96M93-1
	ADAD1	NM_001159285.2		c.355A>G	p.Thr119Ala	missense	Exon 3 of 12	NP_001152757.1	A0A140VKH5
	ADAD1	NM_001159295.2		c.301A>G	p.Thr101Ala	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.355A>G	p.Thr119Ala	missense	Exon 4 of 13	ENSP00000296513.2	Q96M93-1
	ADAD1	ENST00000388724.6	TSL:1	c.355A>G	p.Thr119Ala	missense	Exon 3 of 12	ENSP00000373376.2	Q96M93-2
	ADAD1	ENST00000388725.2	TSL:2	c.301A>G	p.Thr101Ala	missense	Exon 3 of 12	ENSP00000373377.2	Q96M93-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152248 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000668 AC: 13 AN: 194520 AF XY: 0.0000932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000611

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000428 AC: 60 AN: 1400252 Hom.: 0 Cov.: 31 AF XY: 0.0000503 AC XY: 35 AN XY: 695264

African (AFR) AF: 0.00 AC: 0 AN: 29158

American (AMR) AF: 0.00 AC: 0 AN: 25776

Ashkenazi Jewish (ASJ) AF: 0.0000853 AC: 2 AN: 23434

East Asian (EAS) AF: 0.00 AC: 0 AN: 37256

South Asian (SAS) AF: 0.000396 AC: 30 AN: 75696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52574

Middle Eastern (MID) AF: 0.00163 AC: 9 AN: 5528

European-Non Finnish (NFE) AF: 0.0000128 AC: 14 AN: 1093370

Other (OTH) AF: 0.0000870 AC: 5 AN: 57460

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000824 AC: 10

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	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0019
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.23	T
Sift4G	Benign	0.096	T
Polyphen		0.070	B
Vest4		0.091
MutPred		0.38		Loss of glycosylation at T119 (P = 0.088)
MVP		0.31
MPC		0.15
ClinPred		0.052	T
GERP RS		5.6
Varity_R		0.075
gMVP		0.41
Mutation Taster		=72/28	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: rs200548828; hg19: chr4-123302329;