4-122396264-T-G

Variant names:

• chr4-122396264-T-G
• rs766697064
• NM_139243.4:c.611T>G

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.611T>G​(p.Ile204Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,589,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. I204T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADAD1 NM_139243.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• 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=0.111260355).

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.611T>G	p.Ile204Ser	missense	Exon 7 of 13	NP_640336.1	Q96M93-1
	ADAD1	NM_001159285.2		c.611T>G	p.Ile204Ser	missense	Exon 6 of 12	NP_001152757.1	A0A140VKH5
	ADAD1	NM_001159295.2		c.557T>G	p.Ile186Ser	missense	Exon 6 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.611T>G	p.Ile204Ser	missense	Exon 7 of 13	ENSP00000296513.2	Q96M93-1
	ADAD1	ENST00000388724.6	TSL:1	c.611T>G	p.Ile204Ser	missense	Exon 6 of 12	ENSP00000373376.2	Q96M93-2
	ADAD1	ENST00000388725.2	TSL:2	c.557T>G	p.Ile186Ser	missense	Exon 6 of 12	ENSP00000373377.2	Q96M93-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437250 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 714408

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32334

American (AMR) AF: 0.00 AC: 0 AN: 40444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 38802

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102306

Other (OTH) AF: 0.00 AC: 0 AN: 59308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.13
Sift	Benign	0.093	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.56		Gain of disorder (P = 0.0051)
MVP		0.54
MPC		0.20
ClinPred		0.048	T
GERP RS		2.2
Varity_R		0.095
gMVP		0.47
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs766697064; hg19: chr4-123317419;