rs730882213

Positions:

• chr19-1912477-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 2.06

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 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. Variant chr19-1912477-G-A is described in Lovd as [Pathogenic]. Variant chr19-1912477-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAT3	NM_138422.4	c.430G>A	p.Val144Met	missense_variant	2/2	ENST00000329478.4
SCAMP4	NM_079834.4	c.-41-2502G>A		intron_variant		ENST00000316097.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAT3	ENST00000329478.4	c.430G>A	p.Val144Met	missense_variant	2/2	1	NM_138422.4	P1
SCAMP4	ENST00000316097.13	c.-41-2502G>A		intron_variant		1	NM_079834.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 0.00000445 AC: 6 AN: 1348432 Hom.: 0 Cov.: 30 AF XY: 0.00000601 AC XY: 4 AN XY: 665022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000315

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000282

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152018 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-strabismus syndrome Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breakthrough Genomics, Breakthrough Genomics	-	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]. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, no assertion criteria provided	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	research	Department of Biochemistry, Faculty of Medicine, University of Khartoum	Mar 25, 2021	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). -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2023	Also known as p.V128M; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32860008, 31130284, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
REVEL	Uncertain	0.30
Sift4G	Uncertain	0.0050	D
Vest4		0.86
MVP		0.51
MPC		1.2
ClinPred		0.96	D
GERP RS		4.0
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs730882213; hg19: chr19-1912476;