Genetic Variant ADAD2:p.Leu104Pro (chr16-84191541-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145400.2(ADAD2):c.311T>C(p.Leu104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAD2
NM_001145400.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.559

Variant links:

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]

ADAD2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19629529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAD2	NM_001145400.2 link	c.311T>C	p.Leu104Pro	missense_variant	Exon 1 of 10	ENST00000315906.10	NP_001138872.1	Q8NCV1-1
ADAD2	NM_139174.4 link	c.311T>C	p.Leu104Pro	missense_variant	Exon 1 of 11		NP_631913.3	Q8NCV1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAD2	ENST00000315906.10 link	c.311T>C	p.Leu104Pro	missense_variant	Exon 1 of 10	1	NM_001145400.2	ENSP00000325153.6	Q8NCV1-1
ADAD2	ENST00000268624.7 link	c.311T>C	p.Leu104Pro	missense_variant	Exon 1 of 11	2		ENSP00000268624.3	Q8NCV1-2
ADAD2	ENST00000567685.1 link	c.83T>C	p.Leu28Pro	missense_variant	Exon 1 of 6	3		ENSP00000454950.1	H3BNP6
ADAD2	ENST00000567413.1 link	n.351T>C		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688416

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.311T>C (p.L104P) alteration is located in exon 1 (coding exon 1) of the ADAD2 gene. This alteration results from a T to C substitution at nucleotide position 311, causing the leucine (L) at amino acid position 104 to be replaced by a proline (P). 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

0.089

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0037

.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.095

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.081

T;T

Polyphen

1.0

D;D

Vest4

0.42

MutPred

0.42

Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);

MVP

0.57

ClinPred

0.44

GERP RS

1.7

Varity_R

0.059

gMVP

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over