rs752360082

Variant names:

• chr19-1912069-TGTCTCCCACAGTCG-T
• rs752360082
• NM_138422.4:c.24_37delTCTCCCACAGTCGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_138422.4(ADAT3):​c.24_37delTCTCCCACAGTCGG​(p.Pro10AlafsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.00019 in 1,440,024 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ADAT3 NM_138422.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.44
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PP5: Variant 19-1912069-TGTCTCCCACAGTCG-T is Pathogenic according to our data. Variant chr19-1912069-TGTCTCCCACAGTCG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1331555.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	c.24_37delTCTCCCACAGTCGG	p.Pro10AlafsTer24	frameshift_variant	Exon 2 of 2	ENST00000329478.4	NP_612431.2
SCAMP4	NM_079834.4	c.-41-2908_-41-2895delTCTCCCACAGTCGG		intron_variant	Intron 1 of 6	ENST00000316097.13	NP_524558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAT3	ENST00000329478.4	c.24_37delTCTCCCACAGTCGG	p.Pro10AlafsTer24	frameshift_variant	Exon 2 of 2	1	NM_138422.4	ENSP00000332448.2
SCAMP4	ENST00000316097.13	c.-41-2908_-41-2895delTCTCCCACAGTCGG		intron_variant	Intron 1 of 6	1	NM_079834.4	ENSP00000316007.7

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000596 AC: 3 AN: 50308 AF XY: 0.000109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000202 AC: 260 AN: 1287784 Hom.: 0 AF XY: 0.000196 AC XY: 123 AN XY: 627974

African (AFR) AF: 0.00 AC: 0 AN: 26068

American (AMR) AF: 0.00 AC: 0 AN: 21918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19494

East Asian (EAS) AF: 0.00 AC: 0 AN: 30726

South Asian (SAS) AF: 0.00 AC: 0 AN: 64726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.000249 AC: 257 AN: 1034068

Other (OTH) AF: 0.0000561 AC: 3 AN: 53444

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74384

African (AFR) AF: 0.000169 AC: 7 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000872 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 03, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Intellectual disability-strabismus syndrome Pathogenic:1

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=99/101	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs752360082; hg19: chr19-1912068;