16-84191489-T-G

Variant names:

• chr16-84191489-T-G
• NM_001145400.2:c.259T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145400.2(ADAD2):​c.259T>G​(p.Leu87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAD2 NM_001145400.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.11

Genes affected

ADAD2 (HGNC:30714): (adenosine deaminase domain containing 2) 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 be active in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039983213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAD2	NM_001145400.2	c.259T>G	p.Leu87Val	missense_variant	Exon 1 of 10	ENST00000315906.10	NP_001138872.1
ADAD2	NM_139174.4	c.259T>G	p.Leu87Val	missense_variant	Exon 1 of 11		NP_631913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAD2	ENST00000315906.10	c.259T>G	p.Leu87Val	missense_variant	Exon 1 of 10	1	NM_001145400.2	ENSP00000325153.6
ADAD2	ENST00000268624.7	c.259T>G	p.Leu87Val	missense_variant	Exon 1 of 11	2		ENSP00000268624.3
ADAD2	ENST00000567685.1	c.31T>G	p.Leu11Val	missense_variant	Exon 1 of 6	3		ENSP00000454950.1
ADAD2	ENST00000567413.1	n.299T>G		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388058 Hom.: 0 Cov.: 38 AF XY: 0.00000292 AC XY: 2 AN XY: 684714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259T>G (p.L87V) alteration is located in exon 1 (coding exon 1) of the ADAD2 gene. This alteration results from a T to G substitution at nucleotide position 259, causing the leucine (L) at amino acid position 87 to be replaced by a valine (V). 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	0.066
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0030
DANN	Benign	0.59
DEOGEN2	Benign	0.0019	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.011
Sift	Benign	0.47	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0090	B;B
Vest4		0.057
MutPred		0.34		Gain of catalytic residue at L87 (P = 0.0152);Gain of catalytic residue at L87 (P = 0.0152);
MVP		0.076
ClinPred		0.27	T
GERP RS		-3.2
Varity_R		0.032
gMVP		0.070

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-84225095;