4-122396290-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_139243.4(ADAD1):c.637G>A(p.Val213Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,597,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ADAD1 NM_139243.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.074662834).
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAD1	NM_139243.4	c.637G>A	p.Val213Ile	missense_variant	7/13	ENST00000296513.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAD1	ENST00000296513.7	c.637G>A	p.Val213Ile	missense_variant	7/13	2	NM_139243.4	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000461 AC: 11 AN: 238534 Hom.: 0 AF XY: 0.0000543 AC XY: 7 AN XY: 129004

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000228 AC: 33 AN: 1445072 Hom.: 0 Cov.: 29 AF XY: 0.0000209 AC XY: 15 AN XY: 718484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0000364

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.637G>A (p.V213I) alteration is located in exon 7 (coding exon 5) of the ADAD1 gene. This alteration results from a G to A substitution at nucleotide position 637, causing the valine (V) at amino acid position 213 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	N;.;N;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.056	B;.;B;.
Vest4		0.23
MutPred		0.63		Loss of methylation at K214 (P = 0.0835);Loss of methylation at K214 (P = 0.0835);Loss of methylation at K214 (P = 0.0835);.;
MVP		0.19
MPC		0.11
ClinPred		0.039	T
GERP RS		5.1
Varity_R		0.046
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs533027008; hg19: chr4-123317445; COSMIC: COSV56646858;