4-122381093-C-A

Variant names:

• chr4-122381093-C-A
• rs771646303
• NM_139243.4:c.274C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139243.4(ADAD1):​c.274C>A​(p.Arg92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAD1 NM_139243.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18956).

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.274C>A	p.Arg92Ser	missense	Exon 4 of 13	NP_640336.1	Q96M93-1
	ADAD1	NM_001159285.2		c.274C>A	p.Arg92Ser	missense	Exon 3 of 12	NP_001152757.1	A0A140VKH5
	ADAD1	NM_001159295.2		c.220C>A	p.Arg74Ser	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.274C>A	p.Arg92Ser	missense	Exon 4 of 13	ENSP00000296513.2	Q96M93-1
	ADAD1	ENST00000388724.6	TSL:1	c.274C>A	p.Arg92Ser	missense	Exon 3 of 12	ENSP00000373376.2	Q96M93-2
	ADAD1	ENST00000388725.2	TSL:2	c.220C>A	p.Arg74Ser	missense	Exon 3 of 12	ENSP00000373377.2	Q96M93-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454272 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 723238

African (AFR) AF: 0.00 AC: 0 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 42332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110532

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.18
Sift	Benign	0.077	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.39
MutPred		0.54		Loss of catalytic residue at R92 (P = 0.0026)
MVP		0.15
MPC		0.26
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.17
gMVP		0.43
Mutation Taster		=83/17	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: rs771646303; hg19: chr4-123302248;