rs730882213

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_138422.4(ADAT3):c.430G>A(p.Val144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,500,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

ADAT3
NM_138422.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 2.06

Publications

21 publications found

Variant links:

Genes affected

ADAT3 (HGNC:25151): (adenosine deaminase tRNA specific 3) This gene encodes a subunit of a tRNA-specific adenosine deaminase. This heterodimeric enzyme converts adenosine to inosine in the tRNA anticodon. A mutation in this gene causes a syndrome characterized by intellectual disability and strabismus. This gene shares its 5' exon with the overlapping gene, secretory carrier membrane protein 4 (Gene ID: 113178). [provided by RefSeq, Jul 2016]

ADAT3 links:

SCAMP4 (HGNC:30385): (secretory carrier membrane protein 4) Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane proteins implicated in membrane trafficking. Most SCAMPs (e.g., SCAMP1; MIM 606911) have N-terminal cytoplasmic NPF (arg-pro-phe) repeats, 4 central transmembrane regions, and a short C-terminal cytoplasmic tail. These SCAMPs likely have a role in endocytosis that is mediated by their NPF repeats. Other SCAMPs, such as SCAMP4, lack the NPF repeats and are therefore unlikely to function in endocytosis (summary by Fernandez-Chacon and Sudhof, 2000 [PubMed 11050114]).[supplied by OMIM, Feb 2011]

SCAMP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

PP5

Variant 19-1912477-G-A is Pathogenic according to our data. Variant chr19-1912477-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAT3	NM_138422.4 link	c.430G>A	p.Val144Met	missense_variant	Exon 2 of 2	ENST00000329478.4	NP_612431.2	Q96EY9D6W601
SCAMP4	NM_079834.4 link	c.-41-2502G>A		intron_variant	Intron 1 of 6	ENST00000316097.13	NP_524558.1	Q969E2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAT3	ENST00000329478.4 link	c.430G>A	p.Val144Met	missense_variant	Exon 2 of 2	1	NM_138422.4	ENSP00000332448.2		D6W601
SCAMP4	ENST00000316097.13 link	c.-41-2502G>A		intron_variant	Intron 1 of 6	1	NM_079834.4	ENSP00000316007.7		Q969E2-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

98236

AF XY:

0.0000182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000152

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000445

AC:

AN:

1348432

Hom.:

Cov.:

AF XY:

0.00000601

AC XY:

AN XY:

665022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27406

American (AMR)

AF:

0.00

AC:

AN:

31290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23740

East Asian (EAS)

AF:

0.0000315

AC:

AN:

31736

South Asian (SAS)

AF:

0.00

AC:

AN:

75588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33258

Middle Eastern (MID)

AF:

0.000196

AC:

AN:

5106

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1064228

Other (OTH)

AF:

0.0000178

AC:

AN:

56080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67966

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability-strabismus syndrome

Pathogenic:16

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also have mental retardation was a carrier for this variant. The p.Val144Met variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2 -

Jun 23, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously reported in patients with intellectual disability and considered as founder mutation in the Saudi Arabian population [PMID: 26842963, 23620220, 32214227]. Functional studies using cell lines derived from intellectual disability-affected individuals showed a severe reduction in tRNA deaminase activity [PMID: 31263000]. -

Institute of Human Genetics, University Hospital of Duesseldorf

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hadassah Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 25, 2021

Department of Biochemistry, Faculty of Medicine, University of Khartoum

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's status in the patients using Sanger sequencing and detected it in a heterozygous status in their parents. Multiple reports previously classified the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) as pathogenic (Alazami et al., 2013; El-Hattab et al., 2016). -

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jul 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.V128M; This variant is associated with the following publications: (PMID: 32860008, 31130284, 37644014, 34374989, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220, 38168508) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neurodevelopmental disorder with brain abnormalities

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM3,PS3,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.42

PhyloP100

2.1

PrimateAI

Pathogenic

0.89

REVEL

Uncertain

0.30

Sift4G

Uncertain

0.0050

Vest4

0.86

MVP

0.51

MPC

1.2

ClinPred

0.96

GERP RS

4.0

gMVP

0.65

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

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

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rs730882213

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over